{"gene":"PF3D7_0731500","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":1985,"finding":"EBA-175 (175-kDa antigen) binds to human erythrocytes susceptible to invasion in a strain-specific manner, and also binds to merozoites. Erythrocytes coated with EBA-175 from one strain were partially resistant to invasion by heterologous-strain merozoites, suggesting EBA-175 acts as a bridging receptor between erythrocytes and merozoites.","method":"Erythrocyte binding assay with culture supernatants; cross-strain binding inhibition of merozoite invasion in vitro","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional inhibition assays, single lab but multiple experimental approaches","pmids":["3901257"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Camp, FCR-3"}]},{"year":1990,"finding":"EBA-175 is encoded by a single open reading frame of 1,435 amino acids. A synthetic peptide (EBA-peptide 4, residues 1062-1103) elicited antibodies in rabbits that inhibited merozoite invasion of erythrocytes in vitro by ~80% and blocked EBA-175 binding to erythrocytes, demonstrating this region is surface-exposed and functionally important.","method":"DNA sequencing of the EBA-175 gene; immunization with synthetic peptide; invasion inhibition assay; erythrocyte binding inhibition assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — gene sequencing combined with functional in vitro invasion and binding inhibition assays in a single study","pmids":["2229177"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1990,"finding":"EBA-175 is expressed during schizogony as a 190-kDa precursor in the cell pellet, processed to a 175-kDa form that is released into culture supernatant upon schizont rupture. Release is inhibited by the protease inhibitors chymostatin and leupeptin, indicating proteolytic processing is required for shedding.","method":"Western blot, isoelectric focusing, fractionation of schizont-infected erythrocytes, protease inhibitor treatment","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation with protease inhibitors, single lab, multiple methods","pmids":["2194125"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"finding":"EBA-175 binds specifically to the terminal Neu5Ac(α2-3)Gal sequences on O-linked tetrasaccharides of glycophorin A. Binding was competitively inhibited by Neu5Ac(α2-3)Gal-containing oligosaccharides but not by Neu5Ac(α2-6)Gal linkages. EBA-175 bound tightly enough to glycophorin A to be co-precipitated with an anti-glycophorin A antibody.","method":"Competitive binding inhibition with soluble oligosaccharides; co-immunoprecipitation with anti-glycophorin A antibody; binding assays with enzyme-modified erythrocytes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous biochemical binding specificity assays with multiple oligosaccharide inhibitors and co-precipitation, replicated across multiple conditions","pmids":["1310320"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"finding":"EBA-175 binding to mouse erythrocytes (which naturally contain Neu5,9Ac2) is increased when the C-9 acetyl group is removed by influenza C virus esterase (converting Neu5,9Ac2 to Neu5Ac), demonstrating that EBA-175 discriminates between Neu5Ac and Neu5,9Ac2 and that sialic acid is a structural component of the invasion receptor.","method":"EBA-175 binding assay to mouse erythrocytes treated with sialidase or influenza C virus esterase; invasion assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and invasion assays with chemically defined enzyme treatments, single lab","pmids":["1565137"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"Region II of EBA-175, a cysteine-rich domain, is the erythrocyte-binding domain. When expressed on COS cells, Region II bound specifically to glycophorin A but not glycophorin B, and binding required both sialic acid and the peptide backbone of glycophorin A.","method":"Expression of truncated EBA-175 constructs on COS cells; erythrocyte binding assay with glycophorin-variant erythrocytes","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mapping via truncation expression on COS cells with specific receptor characterization; widely replicated finding","pmids":["8009226"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"EBA-175 binds predominantly to glycophorin A (not glycophorin B) based on binding assays using glycophorin A-deficient erythrocytes. The glycophorin B invasion pathway uses a different parasite ligand, distinct from EBA-175.","method":"Erythrocyte binding assay with glycophorin-deficient erythrocytes; enzyme-treated erythrocyte invasion assays","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with genetically defined receptor-deficient cells, single lab, multiple conditions","pmids":["8078523"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2000,"finding":"Targeted disruption of the 3'-cysteine rich region, transmembrane, and cytoplasmic domains of EBA-175 (in W2mef) did not affect protein expression level or subcellular localization, nor the release of soluble EBA-175 after schizont rupture. However, disruption functionally inactivated the EBA-175/glycophorin A invasion route, causing mutant parasites to switch stably to sialic acid-independent invasion (~85% of invasion).","method":"Targeted gene disruption; Western blot for protein expression; subcellular localization analysis; sialic acid-dependent invasion assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disruption with defined invasion phenotype readout, multiple parasite lines tested","pmids":["10861015"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"W2mef"}]},{"year":2000,"finding":"Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone (which uses a sialic acid-independent invasion pathway) did not affect erythrocyte invasion rates. The truncated protein remained localized to the apical end near micronemes, indicating that the C-terminal region 6 and cytoplasmic domain are not required for microneme trafficking in this strain background.","method":"Targeted gene disruption; immunofluorescence localization; invasion assay with enzyme-treated erythrocytes","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single gene disruption with localization and invasion phenotype, single lab","pmids":["10989151"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2/Nm"}]},{"year":2002,"finding":"EBA-175 and PfAMA1 are both localized to microneme organelles but translocate to the merozoite surface independently of each other, as demonstrated by tracking processed versus unprocessed forms in developing schizonts.","method":"Immunofluorescence; Western blot tracking processing and surface expression of EBA-175 and AMA1 in parallel","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — colocalization and parallel tracking of two proteins, single lab, indirect evidence of independence","pmids":["12228305"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"EBA-175 transcript (eba-175) is expressed in a tightly controlled, stage-specific manner, peaking only at the end of schizont development, as demonstrated by quantitative real-time RT-PCR in synchronized parasites.","method":"Quantitative real-time RT-PCR (TaqMan) on temperature-synchronized P. falciparum","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative, stage-resolved transcript analysis in synchronized parasites, single lab","pmids":["12000842"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Genetic knockout or truncation of EBA-175 in W2mef parasites (which are sialic acid-dependent) caused a switch to sialic acid-independent invasion, while 3D7 parasites lacking EBA-175 showed no change in sialic acid-independent invasion ability. Both W2mef and 3D7 EBA-175 knockout lines invaded chymotrypsin-treated erythrocytes inefficiently, identifying the EBA-175/glycophorin A interaction as the major chymotrypsin-resistant invasion pathway.","method":"Gene knockout and truncation in two P. falciparum strains; invasion assays with neuraminidase-, chymotrypsin-, and trypsin-treated erythrocytes","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic lines (knockout and truncation) in two distinct parasite strains with defined invasion pathway phenotypes","pmids":["12672957"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"W2mef, 3D7"}]},{"year":2003,"finding":"The cytoplasmic domain of EBA-175 encodes information essential for merozoite invasion function but is dispensable for trafficking of the protein to micronemes. Furthermore, the cytoplasmic domain of TRAP can substitute for that of EBA-175, restoring invasion function, indicating a shared cytoplasmic machinery for invasion regardless of parasite stage or host cell type.","method":"Domain-swap transgenic parasites; immunofluorescence localization; invasion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-swap experiments with functional rescue and localization assays, clear mechanistic dissection","pmids":["12876279"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Crystal structure of EBA-175 region II (RII) was solved at atomic resolution. RII forms a dimer with two prominent channels containing four of six glycan-binding sites. Each monomer consists of two Duffy binding-like (DBL) domains (F1 and F2), with F2 making the majority of glycan contacts. Sialylated glycan (Neu5Ac-containing) binding sites were identified in a complex of RII with a glycan containing essential components for receptor binding.","method":"X-ray crystallography; RII-glycan co-crystal structure","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure with ligand complex, identifying glycan-binding sites and dimer organization","pmids":["16051144"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"P. falciparum EBA-175 evolved to preferentially recognize N-acetylneuraminic acid (Neu5Ac), the predominant sialic acid on human erythrocytes (humans having lost the ability to synthesize N-glycolylneuraminic acid, Neu5Gc). This was demonstrated using erythroleukemia cells with experimentally manipulated sialic acid content, showing that P. falciparum EBA-175 binds human-type Neu5Ac-bearing cells efficiently, whereas P. reichenowi EBA-175 prefers Neu5Gc-bearing cells.","method":"Modified sialic acid binding assay; erythroleukemia cells with manipulated Sia content; binding of EBA-175 orthologs from P. falciparum and P. reichenowi","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparative binding assays with biochemically manipulated cells, single lab","pmids":["16126901"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium reichenowi","strain":""}]},{"year":2006,"finding":"EBA-175 is cleaved within its transmembrane domain by PfROM4, a rhomboid intramembrane protease localized to the merozoite plasma membrane, at a site conserved across the DBL-EBP family. Shedding of EBA-175 from the merozoite surface occurs around the time of erythrocyte invasion. Mutations within the EBA-175 transmembrane domain that abolish PfROM4 cleavage prevented parasite growth.","method":"Heterologous cleavage assay with Plasmodium and model rhomboid proteases; mutagenesis of the EBA-175 transmembrane domain; transgenic parasite growth assay; immunofluorescence timing of shedding","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic cleavage assay, transmembrane domain mutagenesis, and growth phenotype in a single study","pmids":["17000879"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"EBA-175 (along with EBA-140 and EBA-181) is trafficked to micronemes via a conserved cysteine-rich region in the ectodomain, not through its cytoplasmic or transmembrane domains. Correct sorting to micronemes is dependent on accurate timing of expression, as shown by analysis of EBA-GFP chimeric protein distribution in transgenic parasites.","method":"Transgenic EBA-GFP chimeric proteins; immunofluorescence localization; domain-swap analysis in P. falciparum","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic chimeric protein approach with localization readout, multiple EBL family members tested, single lab","pmids":["16935855"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PfROM4 cleaved EBA-175 (along with TRAP, CTRP, MTRAP, PFF0800c, BAEBL, JESEBL, MAEBL, Rh1, Rh2a, Rh2b, Rh4) efficiently in a heterologous assay; cleavage was dependent on the adhesin transmembrane domains. Swapping transmembrane regions between BAEBL and AMA1 switched the cleavage preferences of PfROMs 1 and 4, confirming that the transmembrane domain determines substrate specificity.","method":"Heterologous rhomboid protease cleavage assay; transmembrane domain swap experiments","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic cleavage assay with domain swaps establishing specificity determinants, single lab","pmids":["17040128"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Protein disulfide isomerase PfPDI-8 facilitates disulfide-dependent conformational folding of EBA-175 in vitro, demonstrated by biochemical reconstitution showing PfPDI-8 is a potent oxido-reductase that assists in the proper folding of recombinant EBA-175.","method":"Biochemical oxido-reductase assay; in vitro protein folding reconstitution with recombinant PfPDI-8 and EBA-175","journal":"International journal for parasitology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution assay, single lab, single method","pmids":["16806221"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Exposure of P. falciparum merozoites to low potassium ion concentrations (as in blood plasma) triggers a rise in cytosolic calcium via a phospholipase C-mediated pathway, which then drives secretion of EBA-175 from micronemes to the merozoite surface. Subsequently, EBA-175 interaction with its receptor glycophorin A restores basal cytosolic calcium levels and triggers rhoptry protein release.","method":"Time-lapse video microscopy of intracellular calcium in merozoites; flow cytometry for cytosolic calcium and surface expression of apical organelle proteins; pharmacological inhibition of phospholipase C","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, flow cytometry, pharmacological inhibition) dissecting sequential signal-triggered secretion, single lab","pmids":["20140184"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"EBA-175, EBA-181, and EBA-140 (EBL proteins) function cooperatively with PfRh (reticulocyte binding-like) proteins in erythrocyte invasion. Loss of EBA-181 function ablates antibody inhibition mediated by PfRh2a/b, and loss of some ebl genes results in upregulation of PfRh family transcripts, demonstrating functional interaction and compensatory regulation between the two families.","method":"Single and double gene knockouts (eba-175, eba-181, eba-140); invasion assays; antibody growth inhibition assays; transcriptional profiling","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple single and double knockout lines with defined functional and transcriptional phenotypes, mechanistic cross-family interaction established","pmids":["21149582"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"Structural basis for antibody inhibition of EBA-175 was established by X-ray crystallography and small-angle X-ray scattering. The potent inhibitory antibody R217 engages critical glycophorin A (GpA)-binding residues and the proposed dimer interface of EBA-175 RII, directly blocking GpA engagement. A weakly inhibitory antibody R218 binds an asparagine-rich surface loop and does not prevent GpA binding.","method":"X-ray crystallography of antibody-RII complexes; small-angle X-ray scattering; direct receptor binding assay; epitope mapping","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of two distinct antibody complexes combined with direct receptor binding assays and functional inhibition data in a single study","pmids":["23717209"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"The full ectodomain of EBA-175 (PfEBA175 FL) binds native glycophorin A with a KD of ~0.26 μM and can self-associate. The region II (RII) fragment alone bound glycophorin A with lower affinity, demonstrating that regions outside the DBL domains are important for GYPA interaction. Antibodies directed to non-DBL regions also contribute to invasion inhibition.","method":"Recombinant expression of full-length EBA-175 ectodomain; quantitative binding assay (SPR or equivalent); invasion inhibition with anti-non-DBL antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative binding assay comparing full-length vs domain fragment, with functional invasion inhibition, single lab","pmids":["24043627"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"EBA-175 interaction with glycophorin A triggers secretion of rhoptry protein PfTRAMP from rhoptries during erythrocyte invasion. Antibodies against PfTRAMP block invasion, and combination of anti-PfTRAMP and anti-EBA-175 antibodies shows additive invasion inhibition, placing EBA-175 upstream of rhoptry protein release in the invasion cascade.","method":"Localization studies (immunofluorescence); invasion inhibition assays with antibody combinations; functional dissection of secretion sequence","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis established through invasion sequence and antibody combination assays, single lab","pmids":["23387921"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"EBA-175 binding to glycophorin A on the erythrocyte surface triggers an increase in cytoskeletal tension and a reduction in the bending modulus of the red cell membrane. The reduction in bending modulus is directly correlated with parasite invasion efficiency, indicating EBA-175 primes the erythrocyte biophysically to facilitate invasion.","method":"Real-time deformability cytometry; flicker spectroscopy; quantitative correlation of membrane biophysical changes with invasion efficiency","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal biophysical methods with functional correlation, single lab","pmids":["28373555"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"EBA-175 binding to glycophorin A activates a phosphorylation cascade in erythrocyte cytoskeletal proteins that alters the viscoelastic properties of the host cell membrane, conditioning it for successful invasion. TRPM7 kinase inhibitors (FTY720 and waixenicin A) block this phosphorylation cascade, inhibiting the deformability change and merozoite invasion.","method":"Erythrocyte deformability assay; phosphoproteomics of EBA-175-treated erythrocytes; pharmacological inhibition of TRPM7 kinase; invasion inhibition assay","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic and functional pharmacological approaches, single lab, mechanistic pathway established","pmids":["28226242"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"Epigenetic repression of eba-175 using a CRISPR/dCas9 system fused to an epigenetic effector domain (erasing histone acetylation at the eba-175 transcription start site) significantly reduced EBA-175 expression and caused a switch in the parasite's invasion pathway, demonstrating that transcriptional regulation of eba-175 controls invasion pathway usage.","method":"CRISPR/dCas9 epigenetic editing (histone deacetylation at eba-175 TSS); RT-PCR/Western blot for expression; invasion pathway assay","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct epigenetic intervention with functional invasion pathway readout, single lab","pmids":["30584102"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"EBA-175 interacts with the erythrocyte transmembrane protein CD44 and induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. P. falciparum invasion is reduced in CD44-null cultured red blood cells. The primary erythrocyte binding of EBA-175 relies on its canonical receptor glycophorin A, with CD44 acting as a coreceptor.","method":"CRISPR/Cas9 knockout of CD44 in primary human hematopoietic stem cells; ex vivo erythropoiesis; invasion assay; binding assay with receptor-deficient cells; phosphorylation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout of host receptor combined with direct binding assay and phosphorylation readout, mechanistic dissection of primary vs coreceptor roles","pmids":["37832027"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"EBA-175 interacts with CD44 on erythrocytes and induces RBC membrane changes that increase accessibility of surface proteins including Basigin, and enhance binding of the PfRH5/PCRCR invasion complex to Basigin. These effects are similar to those of an anti-CD44 cross-linking antibody (BRIC 222), suggesting EBA-175 acts as a functional CD44 cross-linker to coordinate downstream invasion interactions.","method":"Recombinant EBA-175 treatment of RBCs; binding assay for PfRH5/PCRCR to Basigin; flow cytometry for surface protein accessibility; P. falciparum invasion assay with EBA-175 addition","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with recombinant protein, single lab, mechanistic model supported by multiple orthogonal readouts","pmids":["41354647"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Optical tweezer-based quantification showed that interventions disrupting EBA-175-like antigen (PfEBA) family function significantly reduced the force and frequency of merozoite-erythrocyte attachment. Deletion of EBA-175 (PfEBA175) had a significant impact on invasion under flow conditions but not in static culture, establishing PfEBA family proteins (including EBA-175) as central mediators of merozoite attachment.","method":"Optical tweezers direct force measurement of merozoite-erythrocyte attachment; genetically modified parasite lines; invasion assay under flow and static conditions","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel biophysical assay with genetic deletion, single lab, established contribution of EBA-175 to attachment force","pmids":["39312588"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"EBA-175 region II polymorphisms (high sequence variability between strains) do not affect the receptor specificity or the ability of EBA-175 to bind glycophorin A; unlike EBA-140 and EBA-181, EBA-175 shows no variability in its ability to bind its receptor despite high polymorphism in region II.","method":"Erythrocyte binding assays with recombinant region II variants; invasion assays with receptor-deficient erythrocytes","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with multiple allelic variants, single lab, clear negative result for receptor specificity change","pmids":["19204093"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"EBA-175 (PF3D7_0731500) is a P. falciparum microneme protein that is secreted upon low-potassium/calcium signaling to the merozoite surface, where its region II (comprising tandem Duffy binding-like domains F1 and F2 arranged as a dimer) binds Neu5Ac(α2-3)Gal O-linked glycans on glycophorin A of human erythrocytes; this interaction drives biophysical changes (increased cytoskeletal tension, reduced membrane bending modulus) and a CD44-dependent phosphorylation cascade in the erythrocyte that together facilitate invasion, while EBA-175 itself is shed by PfROM4-mediated intramembrane cleavage of its transmembrane domain at around the time of invasion, with its cytoplasmic domain being essential for invasion function (though not for microneme targeting), and loss of EBA-175 function causes parasites to switch to sialic acid-independent invasion pathways."},"narrative":{"mechanistic_narrative":"EBA-175 (PF3D7_0731500) is a Plasmodium falciparum merozoite microneme adhesin that mediates sialic acid-dependent erythrocyte recognition during blood-stage invasion [PMID:3901257, PMID:10861015]. Its erythrocyte-binding activity resides in the cysteine-rich region II (RII), which specifically engages the terminal Neu5Ac(α2-3)Gal sequences of O-linked glycans on glycophorin A, requiring both sialic acid and the glycophorin A peptide backbone [PMID:1310320, PMID:8009226]; RII adopts a two-domain (F1/F2) Duffy binding-like fold that dimerizes to create glycan-binding channels, with F2 making the majority of glycan contacts [PMID:16051144], and full ectodomain contributions outside RII further support glycophorin A engagement [PMID:24043627]. Receptor engagement is not merely adhesive: EBA-175 binding to glycophorin A, with CD44 acting as a coreceptor, drives erythrocyte cytoskeletal phosphorylation, increases cytoskeletal tension and lowers the membrane bending modulus, biophysically priming the red cell for invasion [PMID:28373555, PMID:28226242, PMID:37832027], and functions upstream of downstream invasion signals including calcium restoration and rhoptry protein release [PMID:20140184, PMID:23387921]. Genetic disruption inactivates the EBA-175/glycophorin A route and, in strains such as W2mef, triggers a stable switch to sialic acid-independent invasion, defining EBA-175 as one interchangeable ligand within a redundant invasion-pathway network alongside the PfRh proteins [PMID:10861015, PMID:12672957, PMID:21149582]. EBA-175 is secreted upon a low-potassium/phospholipase C/calcium signal, and is shed from the merozoite surface by the rhomboid protease PfROM4, which cleaves within its transmembrane domain around the time of invasion [PMID:17000879, PMID:20140184].","teleology":[{"year":1985,"claim":"Establishing that a secreted parasite antigen could bridge merozoites and susceptible erythrocytes framed EBA-175 as a candidate invasion ligand rather than a passive surface protein.","evidence":"erythrocyte binding assays with culture supernatants and cross-strain invasion inhibition in vitro","pmids":["3901257"],"confidence":"Medium","gaps":["Molecular receptor not identified","Binding domain within the protein not mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":"Camp, FCR-3"}]},{"year":1990,"claim":"Cloning the single-ORF gene and demonstrating that a surface-exposed peptide region elicits invasion-blocking antibodies connected the protein sequence to functional invasion and binding.","evidence":"gene sequencing plus rabbit immunization with a synthetic peptide followed by invasion and binding inhibition assays","pmids":["2229177"],"confidence":"High","gaps":["Receptor identity unresolved","Precise binding domain not yet delimited"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1990,"claim":"Showing that a 190-kDa precursor is processed to 175 kDa and released at schizont rupture in a protease-dependent manner established that EBA-175 is proteolytically shed.","evidence":"biochemical fractionation, Western blot, and protease inhibitor treatment of schizont-infected erythrocytes","pmids":["2194125"],"confidence":"Medium","gaps":["Responsible protease not identified","Cleavage site not mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"claim":"Defining Neu5Ac(α2-3)Gal on glycophorin A as the binding determinant identified the molecular receptor and its precise glycan linkage requirement.","evidence":"competitive oligosaccharide inhibition, co-immunoprecipitation with anti-glycophorin A, enzyme-modified erythrocyte binding, and influenza C esterase discrimination of Neu5Ac vs Neu5,9Ac2","pmids":["1310320","1565137"],"confidence":"High","gaps":["Contribution of the peptide backbone not yet quantified","Binding domain within EBA-175 not localized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"claim":"Mapping binding to the cysteine-rich region II and to glycophorin A (not B) localized the functional ligand domain and defined receptor specificity.","evidence":"expression of truncated constructs on COS cells and binding assays with glycophorin-variant and glycophorin-deficient erythrocytes","pmids":["8009226","8078523"],"confidence":"High","gaps":["Atomic basis of glycan recognition unknown","Role of the glycophorin B ligand not attributable to EBA-175"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2000,"claim":"Genetic disruption showed EBA-175 is functionally dispensable in some backgrounds because parasites switch to sialic acid-independent invasion, revealing invasion-pathway redundancy.","evidence":"targeted gene disruption in W2mef and Dd2/Nm with expression, localization, and sialic-acid-dependence invasion readouts","pmids":["10861015","10989151"],"confidence":"High","gaps":["Molecular basis of the pathway switch not defined","Compensating ligands not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":"W2mef"},{"species":"Plasmodium falciparum","strain":"Dd2/Nm"}]},{"year":2002,"claim":"Stage-specific transcription peaking late in schizogony and independent trafficking of EBA-175 relative to AMA1 clarified the timing and organellar logistics of the ligand's deployment.","evidence":"quantitative RT-PCR in synchronized parasites and parallel immunofluorescence/Western tracking of EBA-175 and AMA1 processing","pmids":["12000842","12228305"],"confidence":"Medium","gaps":["Transcriptional regulators not identified","Trafficking signal not yet mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Domain-swap and knockout experiments dissected functional domains: the cytoplasmic tail carries invasion-essential (but not trafficking) information and is interchangeable with TRAP, while the EBA-175/glycophorin A axis is the major chymotrypsin-resistant pathway.","evidence":"domain-swap transgenics with functional rescue and localization, plus knockout/truncation lines assayed against enzyme-treated erythrocytes across strains","pmids":["12876279","12672957"],"confidence":"High","gaps":["Cytoplasmic-domain effector machinery not identified","Strain-dependence of pathway switching unexplained"],"attribution":[{"species":"Plasmodium falciparum","strain":"W2mef, 3D7"}]},{"year":2005,"claim":"The atomic structure of RII revealed a two-DBL-domain (F1/F2) monomer that dimerizes to form glycan-binding channels, providing the structural mechanism of sialylated-glycan recognition and its evolved preference for human Neu5Ac.","evidence":"X-ray crystallography of RII-glycan complex and comparative sialic-acid binding assays with P. falciparum and P. reichenowi orthologs","pmids":["16051144","16126901"],"confidence":"High","gaps":["Structure of full ectodomain-glycophorin A complex unresolved","Coupling of binding to signaling not structurally defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium reichenowi","strain":""}]},{"year":2006,"claim":"Identifying PfROM4 as the intramembrane protease that cleaves the EBA-175 transmembrane domain, along with the cysteine-rich ectodomain microneme-targeting signal, resolved how EBA-175 is trafficked and shed and showed cleavage is essential for growth.","evidence":"heterologous rhomboid cleavage assays, transmembrane mutagenesis and domain swaps, EBA-GFP chimera localization, and in vitro folding with PfPDI-8","pmids":["17000879","16935855","17040128","16806221"],"confidence":"High","gaps":["In vivo timing and regulation of shedding not fully resolved","Functional requirement of PfPDI-8 folding in vivo not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Linking low-potassium/phospholipase-C/calcium signaling to EBA-175 secretion, and cooperative function with PfRh proteins, placed EBA-175 within an ordered, network-regulated invasion cascade.","evidence":"live calcium imaging, flow cytometry, PLC inhibition, and single/double ebl-PfRh knockouts with invasion and transcriptional profiling","pmids":["20140184","21149582"],"confidence":"High","gaps":["Molecular sensor coupling secretion to calcium not identified","Mechanism of cross-family transcriptional compensation unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Antibody-complex structures, full-ectodomain binding quantification, and epistasis with PfTRAMP defined how inhibitory antibodies block glycophorin A engagement and positioned EBA-175 upstream of rhoptry release.","evidence":"crystallography and SAXS of RII-antibody complexes, SPR-type binding of full-length ectodomain, and invasion inhibition with antibody combinations","pmids":["23717209","24043627","23387921"],"confidence":"High","gaps":["Signal relayed from receptor binding to rhoptry secretion not molecularly traced","Role of non-DBL regions in vivo not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Demonstrating that EBA-175-glycophorin A engagement drives erythrocyte cytoskeletal phosphorylation and measurable biophysical changes reframed EBA-175 as an active signaling ligand that primes the host cell for invasion.","evidence":"deformability cytometry, flicker spectroscopy, phosphoproteomics, and TRPM7 kinase inhibition with invasion readouts","pmids":["28373555","28226242"],"confidence":"Medium","gaps":["Host receptor coupling the ligand to TRPM7 signaling not defined at this stage","Causal chain from tension change to invasion not fully resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Epigenetic silencing of eba-175 showed that transcriptional control of the ligand itself governs invasion-pathway usage, connecting gene regulation to phenotypic pathway switching.","evidence":"CRISPR/dCas9 epigenetic editing at the eba-175 TSS with expression and invasion-pathway assays","pmids":["30584102"],"confidence":"Medium","gaps":["Endogenous epigenetic regulators not identified","Trigger for physiological switching unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Identifying CD44 as a coreceptor and showing EBA-175 acts as a CD44 cross-linker that increases Basigin accessibility for the PfRH5/PCRCR complex mechanistically linked EBA-175 binding to downstream invasion-complex engagement and to attachment force.","evidence":"CD44 knockout erythroid cells, recombinant EBA-175 treatment with Basigin/PfRH5 binding and surface-accessibility readouts, and optical-tweezer force measurements of attachment","pmids":["37832027","41354647","39312588"],"confidence":"High","gaps":["Structural basis of EBA-175-CD44 interaction unknown","How glycophorin A and CD44 engagement are integrated not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How receptor engagement is mechanistically transduced into the erythrocyte signaling and membrane-remodeling events, and how the cytoplasmic-tail invasion machinery operates, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Molecular link from glycophorin A/CD44 binding to the erythrocyte phosphorylation cascade not fully defined","Effectors engaged by the EBA-175 cytoplasmic domain unidentified","Integration of glycophorin A, CD44, and Basigin engagement into a single invasion mechanism unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["EBA-175 region II forms a homodimer that creates glycan-binding channels [#13]","Full-length EBA-175 ectodomain can self-associate [#22]"],"partners":["GLYCOPHORIN A (HUMAN ERYTHROCYTE RECEPTOR, NEU5AC(Α2-3)GAL GLYCANS) [#3, #5, #6, #22]","CD44 (ERYTHROCYTE CORECEPTOR / CROSS-LINKING TARGET) [#27, #28]","PFROM4 (RHOMBOID INTRAMEMBRANE PROTEASE THAT CLEAVES THE EBA-175 TM DOMAIN) [#15, #17]","PFPDI-8 (PROTEIN DISULFIDE ISOMERASE ASSISTING EBA-175 FOLDING IN VITRO) [#18]","PFRH FAMILY PROTEINS (COOPERATIVE/COMPENSATORY INVASION FUNCTION) [#20]","PFTRAMP (RHOPTRY PROTEIN RELEASED DOWNSTREAM OF EBA-175 ENGAGEMENT) [#23]","PFRH5/PCRCR COMPLEX AND BASIGIN (ACCESSIBILITY ENHANCED BY EBA-175-CD44 ACTION) [#28]"],"other_free_text":["EBA-175 binding to glycophorin A triggers erythrocyte cytoskeletal phosphorylation, increased cytoskeletal tension and reduced membrane bending modulus, priming the cell for invasion [#24, #25]","Secretion of EBA-175 from micronemes is triggered by low-potassium/phospholipase-C-mediated cytosolic calcium rise; receptor engagement then restores basal calcium and triggers rhoptry release [#19, #23]","Loss of EBA-175 function causes strain-dependent switching to sialic acid-independent invasion [#7, #11]","The cytoplasmic domain is essential for invasion function but dispensable for microneme trafficking, and is interchangeable with the TRAP cytoplasmic domain [#12]","Region II is highly polymorphic between strains, yet this polymorphism does not alter receptor specificity or glycophorin A binding [#30]","P. falciparum EBA-175 evolved to prefer human Neu5Ac over Neu5Gc, unlike the P. reichenowi ortholog [#14]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"8009226","id":"PMC_8009226","title":"Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum.","date":"1994","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8009226","citation_count":477,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18316390","id":"PMC_18316390","title":"Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria.","date":"2008","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18316390","citation_count":324,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3901257","id":"PMC_3901257","title":"A Plasmodium falciparum antigen that binds to host erythrocytes and merozoites.","date":"1985","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/3901257","citation_count":309,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16051144","id":"PMC_16051144","title":"Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16051144","citation_count":273,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20098724","id":"PMC_20098724","title":"The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: A systematic review and meta-analysis.","date":"2010","source":"PLoS medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20098724","citation_count":271,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20140184","id":"PMC_20140184","title":"Distinct external signals trigger sequential release of apical organelles during erythrocyte invasion by malaria parasites.","date":"2010","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/20140184","citation_count":225,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9584096","id":"PMC_9584096","title":"Genetic polymorphism and natural selection in the malaria parasite Plasmodium falciparum.","date":"1998","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9584096","citation_count":213,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2229177","id":"PMC_2229177","title":"Primary structure of the 175K Plasmodium falciparum erythrocyte binding antigen and identification of a peptide which elicits antibodies that inhibit malaria merozoite invasion.","date":"1990","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2229177","citation_count":206,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"1310320","id":"PMC_1310320","title":"A malaria invasion receptor, the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum recognizes the terminal Neu5Ac(alpha 2-3)Gal- sequences of glycophorin A.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1310320","citation_count":206,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16372020","id":"PMC_16372020","title":"Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16372020","citation_count":204,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12672957","id":"PMC_12672957","title":"Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12672957","citation_count":192,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25108687","id":"PMC_25108687","title":"Efficient CRISPR-Cas9-mediated genome editing in Plasmodium falciparum.","date":"2014","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/25108687","citation_count":182,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17040128","id":"PMC_17040128","title":"Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria.","date":"2006","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/17040128","citation_count":180,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10861015","id":"PMC_10861015","title":"Targeted disruption of an erythrocyte binding antigen in Plasmodium falciparum is associated with a switch toward a sialic acid-independent pathway of invasion.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10861015","citation_count":172,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8078523","id":"PMC_8078523","title":"Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes.","date":"1994","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8078523","citation_count":169,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11733572","id":"PMC_11733572","title":"A Plasmodium falciparum homologue of Plasmodium vivax reticulocyte binding protein (PvRBP1) defines a trypsin-resistant erythrocyte invasion pathway.","date":"2001","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11733572","citation_count":169,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20843207","id":"PMC_20843207","title":"Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia.","date":"2010","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/20843207","citation_count":168,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12556470","id":"PMC_12556470","title":"A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12556470","citation_count":153,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17598897","id":"PMC_17598897","title":"IgG antibody responses to Plasmodium falciparum merozoite antigens in Kenyan children have a short half-life.","date":"2007","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/17598897","citation_count":152,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12228305","id":"PMC_12228305","title":"Independent translocation of two micronemal proteins in developing Plasmodium falciparum merozoites.","date":"2002","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12228305","citation_count":152,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17000879","id":"PMC_17000879","title":"Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17000879","citation_count":151,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18064303","id":"PMC_18064303","title":"Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies.","date":"2008","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/18064303","citation_count":150,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16126901","id":"PMC_16126901","title":"Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16126901","citation_count":148,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11309486","id":"PMC_11309486","title":"Characterization of a Plasmodium falciparum erythrocyte-binding protein paralogous to EBA-175.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11309486","citation_count":140,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10531229","id":"PMC_10531229","title":"Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A.","date":"1999","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10531229","citation_count":138,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"1864936","id":"PMC_1864936","title":"Determination of genetic variation within Plasmodium falciparum by using enzymatically amplified DNA from filter paper disks impregnated with whole blood.","date":"1991","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1864936","citation_count":131,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21149582","id":"PMC_21149582","title":"Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites.","date":"2010","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21149582","citation_count":117,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16014863","id":"PMC_16014863","title":"Correlation of high levels of antibodies to multiple pre-erythrocytic Plasmodium falciparum antigens and protection from infection.","date":"2005","source":"The American journal of tropical medicine and hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/16014863","citation_count":104,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12165386","id":"PMC_12165386","title":"Bacterially expressed and refolded receptor binding domain of Plasmodium falciparum EBA-175 elicits invasion inhibitory antibodies.","date":"2002","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/12165386","citation_count":99,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24297912","id":"PMC_24297912","title":"RH5-Basigin interaction plays a major role in the host tropism of Plasmodium falciparum.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24297912","citation_count":98,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20041125","id":"PMC_20041125","title":"Contrasting population structures of the genes encoding ten leading vaccine-candidate antigens of the human malaria parasite, Plasmodium falciparum.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20041125","citation_count":91,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11705894","id":"PMC_11705894","title":"Codon optimization of gene fragments encoding Plasmodium falciparum merzoite proteins enhances DNA vaccine protein expression and immunogenicity in mice.","date":"2001","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11705894","citation_count":91,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"14983041","id":"PMC_14983041","title":"Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14983041","citation_count":85,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12933838","id":"PMC_12933838","title":"Effect of codon optimization on expression levels of a functionally folded malaria vaccine candidate in prokaryotic and eukaryotic expression systems.","date":"2003","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12933838","citation_count":85,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10759080","id":"PMC_10759080","title":"Plasmodium falciparum EBA-175 kDa protein peptides which bind to human red blood cells.","date":"2000","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10759080","citation_count":81,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12654801","id":"PMC_12654801","title":"Erythrocyte invasion phenotypes of Plasmodium falciparum in The Gambia.","date":"2003","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12654801","citation_count":80,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2194125","id":"PMC_2194125","title":"Characterization of the 175-kilodalton erythrocyte binding antigen of Plasmodium falciparum.","date":"1990","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2194125","citation_count":79,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10722589","id":"PMC_10722589","title":"Antibodies against the Plasmodium falciparum receptor binding domain of EBA-175 block invasion pathways that do not involve sialic acids.","date":"2000","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10722589","citation_count":78,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"1565137","id":"PMC_1565137","title":"Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form.","date":"1992","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/1565137","citation_count":77,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15908375","id":"PMC_15908375","title":"Distinct Th1- and Th2-Type prenatal cytokine responses to Plasmodium falciparum erythrocyte invasion ligands.","date":"2005","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15908375","citation_count":75,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21896773","id":"PMC_21896773","title":"Discovery of GAMA, a Plasmodium falciparum merozoite micronemal protein, as a novel blood-stage vaccine candidate antigen.","date":"2011","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21896773","citation_count":69,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12876279","id":"PMC_12876279","title":"The cytoplasmic domain of the Plasmodium falciparum ligand EBA-175 is essential for invasion but not protein trafficking.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12876279","citation_count":68,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17035513","id":"PMC_17035513","title":"Multiplex assay for simultaneous measurement of antibodies to multiple Plasmodium falciparum antigens.","date":"2006","source":"Clinical and vaccine immunology : CVI","url":"https://pubmed.ncbi.nlm.nih.gov/17035513","citation_count":67,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12000842","id":"PMC_12000842","title":"Transcripts of developmentally regulated Plasmodium falciparum genes quantified by real-time RT-PCR.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12000842","citation_count":66,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10992454","id":"PMC_10992454","title":"Analysis of human antibodies to erythrocyte binding antigen 175 of Plasmodium falciparum.","date":"2000","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10992454","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12949139","id":"PMC_12949139","title":"Rapidly evolving genes in human. I. The glycophorins and their possible role in evading malaria parasites.","date":"2003","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/12949139","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28373555","id":"PMC_28373555","title":"Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28373555","citation_count":62,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20050806","id":"PMC_20050806","title":"Erythrocyte invasion and merozoite ligand gene expression in severe and mild Plasmodium falciparum malaria.","date":"2010","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20050806","citation_count":59,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28226242","id":"PMC_28226242","title":"Plasmodium falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28226242","citation_count":58,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22646809","id":"PMC_22646809","title":"Low antibodies against Plasmodium falciparum and imbalanced pro-inflammatory cytokines are associated with severe malaria in Mozambican children: a case-control study.","date":"2012","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/22646809","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23776178","id":"PMC_23776178","title":"Erythrocyte-binding antigens of Plasmodium falciparum are targets of human inhibitory antibodies and function to evade naturally acquired immunity.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23776178","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30584102","id":"PMC_30584102","title":"Epigenetic editing by CRISPR/dCas9 in Plasmodium falciparum.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30584102","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21502513","id":"PMC_21502513","title":"Evidence for erythrocyte-binding antigen 175 as a component of a ligand-blocking blood-stage malaria vaccine.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21502513","citation_count":55,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31234897","id":"PMC_31234897","title":"Erythrocyte glycophorins as receptors for Plasmodium merozoites.","date":"2019","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/31234897","citation_count":54,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23717209","id":"PMC_23717209","title":"Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23717209","citation_count":54,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11463466","id":"PMC_11463466","title":"An EBA175 homologue which is transcribed but not translated in erythrocytic stages of Plasmodium falciparum.","date":"2001","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/11463466","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19204093","id":"PMC_19204093","title":"Polymorphisms in erythrocyte binding antigens 140 and 181 affect function and binding but not receptor specificity in Plasmodium falciparum.","date":"2009","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19204093","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16935855","id":"PMC_16935855","title":"A conserved region in the EBL proteins is implicated in microneme targeting of the malaria parasite Plasmodium falciparum.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16935855","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19614665","id":"PMC_19614665","title":"Reticulocyte binding protein homologues are key adhesins during erythrocyte invasion by Plasmodium falciparum.","date":"2009","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19614665","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16461900","id":"PMC_16461900","title":"The glycophorin C N-linked glycan is a critical component of the ligand for the Plasmodium falciparum erythrocyte receptor BAEBL.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16461900","citation_count":52,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12082132","id":"PMC_12082132","title":"Evolutionary relationships of conserved cysteine-rich motifs in adhesive molecules of malaria parasites.","date":"2002","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/12082132","citation_count":50,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9084043","id":"PMC_9084043","title":"Conservation of structure and function of the erythrocyte-binding domain of Plasmodium falciparum EBA-175.","date":"1997","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9084043","citation_count":50,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21628653","id":"PMC_21628653","title":"Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21628653","citation_count":49,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20702657","id":"PMC_20702657","title":"Safety and immunogenicity of a recombinant nonglycosylated erythrocyte binding antigen 175 Region II malaria vaccine in healthy adults living in an area where malaria is not endemic.","date":"2010","source":"Clinical and vaccine immunology : CVI","url":"https://pubmed.ncbi.nlm.nih.gov/20702657","citation_count":48,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8366884","id":"PMC_8366884","title":"Two alleles of the 175-kilodalton Plasmodium falciparum erythrocyte binding antigen.","date":"1993","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8366884","citation_count":46,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22252876","id":"PMC_22252876","title":"Plasmodium falciparum malaria in the Peruvian Amazon, a region of low transmission, is associated with immunologic memory.","date":"2012","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22252876","citation_count":45,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10989151","id":"PMC_10989151","title":"Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone of Plasmodium falciparum does not affect erythrocyte invasion.","date":"2000","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10989151","citation_count":44,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35108259","id":"PMC_35108259","title":"Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.","date":"2022","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/35108259","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8552672","id":"PMC_8552672","title":"Inhibition of Plasmodium falciparum malaria using antisense oligodeoxynucleotides.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8552672","citation_count":41,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15155670","id":"PMC_15155670","title":"Antibodies against MAEBL ligand domains M1 and M2 inhibit sporozoite development in vitro.","date":"2004","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15155670","citation_count":41,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24043627","id":"PMC_24043627","title":"Biochemical analysis of the Plasmodium falciparum erythrocyte-binding antigen-175 (EBA175)-glycophorin-A interaction: implications for vaccine design.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24043627","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17438038","id":"PMC_17438038","title":"Invasion pathways and malaria severity in Kenyan Plasmodium falciparum clinical isolates.","date":"2007","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17438038","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23387921","id":"PMC_23387921","title":"A thrombospondin structural repeat containing rhoptry protein from Plasmodium falciparum mediates erythrocyte invasion.","date":"2013","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23387921","citation_count":39,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16806221","id":"PMC_16806221","title":"Protein disulfide isomerase assisted protein folding in malaria parasites.","date":"2006","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/16806221","citation_count":39,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21689436","id":"PMC_21689436","title":"Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults.","date":"2011","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/21689436","citation_count":39,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25870227","id":"PMC_25870227","title":"Variation in Plasmodium falciparum erythrocyte invasion phenotypes and merozoite ligand gene expression across different populations in areas of malaria endemicity.","date":"2015","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25870227","citation_count":37,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25271267","id":"PMC_25271267","title":"Malaria and HIV infection in Mozambican pregnant women are associated with reduced transfer of antimalarial antibodies to their newborns.","date":"2014","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25271267","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42190989","id":"PMC_42190989","title":"Plasmodium falciparum invasion ligand gene transcript profiles in different populations.","date":"2026","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/42190989","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41893415","id":"PMC_41893415","title":"Cytokine-Driven Immune Phenotypes at Delivery as Indicators of Malaria Infection Among Primigravidae in Burkina Faso: An Exploratory Analysis.","date":"2026","source":"Tropical medicine and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/41893415","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41849253","id":"PMC_41849253","title":"Microfluidic platform for automatic quantification of malaria parasite invasion under physiological flow conditions.","date":"2026","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/41849253","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42144948","id":"PMC_42144948","title":"The N-terminal region of malaria vaccine candidate asparagine-rich merozoite antigen is immunodominant and targeted by polyreactive antibodies.","date":"2026","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/42144948","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41586363","id":"PMC_41586363","title":"Serological evidence of continued exposure to Plasmodium falciparum among residents in a near-elimination setting.","date":"2026","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41586363","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41354647","id":"PMC_41354647","title":"CD44 cross-linking promotes Plasmodium falciparum invasion.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41354647","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41415367","id":"PMC_41415367","title":"The N-terminal region of malaria vaccine candidate Plasmodium falciparum asparagine-rich merozoite antigen is immunodominant and targeted by polyreactive antibodies.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41415367","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41208999","id":"PMC_41208999","title":"Micro-geographic variation in antigenic diversity of PfEBA-175 region II in asymptomatic Plasmodium falciparum infections in Tanzania.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41208999","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40766538","id":"PMC_40766538","title":"CD44 cross-linking promotes Plasmodium falciparum invasion.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40766538","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39844183","id":"PMC_39844183","title":"Spatiotemporal analysis of Plasmodium falciparum erythrocyte binding antigen-175 gene dimorphism in Ghana.","date":"2025","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/39844183","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39312588","id":"PMC_39312588","title":"Application of optical tweezer technology reveals that PfEBA and PfRH ligands, not PfMSP1, play a central role in Plasmodium falciparum merozoite-erythrocyte attachment.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39312588","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39232787","id":"PMC_39232787","title":"Asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of IgG responses but is associated with a balanced inflammatory cytokine ratio.","date":"2024","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/39232787","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38336647","id":"PMC_38336647","title":"Immune responses to P falciparum antibodies in symptomatic malaria patients with variant hemoglobin genotypes in Ghana.","date":"2024","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38336647","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37624328","id":"PMC_37624328","title":"High Prevalence of Polyclonal Plasmodium falciparum Infections and Association with Poor IgG Antibody Responses in a Hyper-Endemic Area in Cameroon.","date":"2023","source":"Tropical medicine and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/37624328","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37754682","id":"PMC_37754682","title":"Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso.","date":"2023","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/37754682","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37832027","id":"PMC_37832027","title":"Plasmodium falciparum exploits CD44 as a coreceptor for erythrocyte invasion.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/37832027","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EBA175","erythrocyte binding antigen-175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37973970","id":"PMC_37973970","title":"Genetic polymorphism and natural selection of the erythrocyte binding antigen 175 region II in Plasmodium falciparum populations from Myanmar and Vietnam.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37973970","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37061695","id":"PMC_37061695","title":"Mosquito bites and stage-specific antibody responses against Plasmodium falciparum in southern Ghana.","date":"2023","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/37061695","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["erythrocyte binding antigen-175","PfEBA175"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52266,"output_tokens":8533,"usd":0.142397,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16779,"output_tokens":6153,"usd":0.11886,"stage2_stop_reason":"end_turn"},"total_usd":0.261257,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1985,\n      \"finding\": \"EBA-175 (175-kDa antigen) binds to human erythrocytes susceptible to invasion in a strain-specific manner, and also binds to merozoites. Erythrocytes coated with EBA-175 from one strain were partially resistant to invasion by heterologous-strain merozoites, suggesting EBA-175 acts as a bridging receptor between erythrocytes and merozoites.\",\n      \"method\": \"Erythrocyte binding assay with culture supernatants; cross-strain binding inhibition of merozoite invasion in vitro\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional inhibition assays, single lab but multiple experimental approaches\",\n      \"pmids\": [\"3901257\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Camp, FCR-3\"}]\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"EBA-175 is encoded by a single open reading frame of 1,435 amino acids. A synthetic peptide (EBA-peptide 4, residues 1062-1103) elicited antibodies in rabbits that inhibited merozoite invasion of erythrocytes in vitro by ~80% and blocked EBA-175 binding to erythrocytes, demonstrating this region is surface-exposed and functionally important.\",\n      \"method\": \"DNA sequencing of the EBA-175 gene; immunization with synthetic peptide; invasion inhibition assay; erythrocyte binding inhibition assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — gene sequencing combined with functional in vitro invasion and binding inhibition assays in a single study\",\n      \"pmids\": [\"2229177\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"EBA-175 is expressed during schizogony as a 190-kDa precursor in the cell pellet, processed to a 175-kDa form that is released into culture supernatant upon schizont rupture. Release is inhibited by the protease inhibitors chymostatin and leupeptin, indicating proteolytic processing is required for shedding.\",\n      \"method\": \"Western blot, isoelectric focusing, fractionation of schizont-infected erythrocytes, protease inhibitor treatment\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation with protease inhibitors, single lab, multiple methods\",\n      \"pmids\": [\"2194125\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"EBA-175 binds specifically to the terminal Neu5Ac(α2-3)Gal sequences on O-linked tetrasaccharides of glycophorin A. Binding was competitively inhibited by Neu5Ac(α2-3)Gal-containing oligosaccharides but not by Neu5Ac(α2-6)Gal linkages. EBA-175 bound tightly enough to glycophorin A to be co-precipitated with an anti-glycophorin A antibody.\",\n      \"method\": \"Competitive binding inhibition with soluble oligosaccharides; co-immunoprecipitation with anti-glycophorin A antibody; binding assays with enzyme-modified erythrocytes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous biochemical binding specificity assays with multiple oligosaccharide inhibitors and co-precipitation, replicated across multiple conditions\",\n      \"pmids\": [\"1310320\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"EBA-175 binding to mouse erythrocytes (which naturally contain Neu5,9Ac2) is increased when the C-9 acetyl group is removed by influenza C virus esterase (converting Neu5,9Ac2 to Neu5Ac), demonstrating that EBA-175 discriminates between Neu5Ac and Neu5,9Ac2 and that sialic acid is a structural component of the invasion receptor.\",\n      \"method\": \"EBA-175 binding assay to mouse erythrocytes treated with sialidase or influenza C virus esterase; invasion assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and invasion assays with chemically defined enzyme treatments, single lab\",\n      \"pmids\": [\"1565137\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Region II of EBA-175, a cysteine-rich domain, is the erythrocyte-binding domain. When expressed on COS cells, Region II bound specifically to glycophorin A but not glycophorin B, and binding required both sialic acid and the peptide backbone of glycophorin A.\",\n      \"method\": \"Expression of truncated EBA-175 constructs on COS cells; erythrocyte binding assay with glycophorin-variant erythrocytes\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mapping via truncation expression on COS cells with specific receptor characterization; widely replicated finding\",\n      \"pmids\": [\"8009226\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"EBA-175 binds predominantly to glycophorin A (not glycophorin B) based on binding assays using glycophorin A-deficient erythrocytes. The glycophorin B invasion pathway uses a different parasite ligand, distinct from EBA-175.\",\n      \"method\": \"Erythrocyte binding assay with glycophorin-deficient erythrocytes; enzyme-treated erythrocyte invasion assays\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with genetically defined receptor-deficient cells, single lab, multiple conditions\",\n      \"pmids\": [\"8078523\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted disruption of the 3'-cysteine rich region, transmembrane, and cytoplasmic domains of EBA-175 (in W2mef) did not affect protein expression level or subcellular localization, nor the release of soluble EBA-175 after schizont rupture. However, disruption functionally inactivated the EBA-175/glycophorin A invasion route, causing mutant parasites to switch stably to sialic acid-independent invasion (~85% of invasion).\",\n      \"method\": \"Targeted gene disruption; Western blot for protein expression; subcellular localization analysis; sialic acid-dependent invasion assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disruption with defined invasion phenotype readout, multiple parasite lines tested\",\n      \"pmids\": [\"10861015\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"W2mef\"}]\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone (which uses a sialic acid-independent invasion pathway) did not affect erythrocyte invasion rates. The truncated protein remained localized to the apical end near micronemes, indicating that the C-terminal region 6 and cytoplasmic domain are not required for microneme trafficking in this strain background.\",\n      \"method\": \"Targeted gene disruption; immunofluorescence localization; invasion assay with enzyme-treated erythrocytes\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single gene disruption with localization and invasion phenotype, single lab\",\n      \"pmids\": [\"10989151\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2/Nm\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EBA-175 and PfAMA1 are both localized to microneme organelles but translocate to the merozoite surface independently of each other, as demonstrated by tracking processed versus unprocessed forms in developing schizonts.\",\n      \"method\": \"Immunofluorescence; Western blot tracking processing and surface expression of EBA-175 and AMA1 in parallel\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — colocalization and parallel tracking of two proteins, single lab, indirect evidence of independence\",\n      \"pmids\": [\"12228305\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EBA-175 transcript (eba-175) is expressed in a tightly controlled, stage-specific manner, peaking only at the end of schizont development, as demonstrated by quantitative real-time RT-PCR in synchronized parasites.\",\n      \"method\": \"Quantitative real-time RT-PCR (TaqMan) on temperature-synchronized P. falciparum\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative, stage-resolved transcript analysis in synchronized parasites, single lab\",\n      \"pmids\": [\"12000842\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic knockout or truncation of EBA-175 in W2mef parasites (which are sialic acid-dependent) caused a switch to sialic acid-independent invasion, while 3D7 parasites lacking EBA-175 showed no change in sialic acid-independent invasion ability. Both W2mef and 3D7 EBA-175 knockout lines invaded chymotrypsin-treated erythrocytes inefficiently, identifying the EBA-175/glycophorin A interaction as the major chymotrypsin-resistant invasion pathway.\",\n      \"method\": \"Gene knockout and truncation in two P. falciparum strains; invasion assays with neuraminidase-, chymotrypsin-, and trypsin-treated erythrocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic lines (knockout and truncation) in two distinct parasite strains with defined invasion pathway phenotypes\",\n      \"pmids\": [\"12672957\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"W2mef, 3D7\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytoplasmic domain of EBA-175 encodes information essential for merozoite invasion function but is dispensable for trafficking of the protein to micronemes. Furthermore, the cytoplasmic domain of TRAP can substitute for that of EBA-175, restoring invasion function, indicating a shared cytoplasmic machinery for invasion regardless of parasite stage or host cell type.\",\n      \"method\": \"Domain-swap transgenic parasites; immunofluorescence localization; invasion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-swap experiments with functional rescue and localization assays, clear mechanistic dissection\",\n      \"pmids\": [\"12876279\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of EBA-175 region II (RII) was solved at atomic resolution. RII forms a dimer with two prominent channels containing four of six glycan-binding sites. Each monomer consists of two Duffy binding-like (DBL) domains (F1 and F2), with F2 making the majority of glycan contacts. Sialylated glycan (Neu5Ac-containing) binding sites were identified in a complex of RII with a glycan containing essential components for receptor binding.\",\n      \"method\": \"X-ray crystallography; RII-glycan co-crystal structure\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure with ligand complex, identifying glycan-binding sites and dimer organization\",\n      \"pmids\": [\"16051144\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"P. falciparum EBA-175 evolved to preferentially recognize N-acetylneuraminic acid (Neu5Ac), the predominant sialic acid on human erythrocytes (humans having lost the ability to synthesize N-glycolylneuraminic acid, Neu5Gc). This was demonstrated using erythroleukemia cells with experimentally manipulated sialic acid content, showing that P. falciparum EBA-175 binds human-type Neu5Ac-bearing cells efficiently, whereas P. reichenowi EBA-175 prefers Neu5Gc-bearing cells.\",\n      \"method\": \"Modified sialic acid binding assay; erythroleukemia cells with manipulated Sia content; binding of EBA-175 orthologs from P. falciparum and P. reichenowi\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparative binding assays with biochemically manipulated cells, single lab\",\n      \"pmids\": [\"16126901\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium reichenowi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBA-175 is cleaved within its transmembrane domain by PfROM4, a rhomboid intramembrane protease localized to the merozoite plasma membrane, at a site conserved across the DBL-EBP family. Shedding of EBA-175 from the merozoite surface occurs around the time of erythrocyte invasion. Mutations within the EBA-175 transmembrane domain that abolish PfROM4 cleavage prevented parasite growth.\",\n      \"method\": \"Heterologous cleavage assay with Plasmodium and model rhomboid proteases; mutagenesis of the EBA-175 transmembrane domain; transgenic parasite growth assay; immunofluorescence timing of shedding\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic cleavage assay, transmembrane domain mutagenesis, and growth phenotype in a single study\",\n      \"pmids\": [\"17000879\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBA-175 (along with EBA-140 and EBA-181) is trafficked to micronemes via a conserved cysteine-rich region in the ectodomain, not through its cytoplasmic or transmembrane domains. Correct sorting to micronemes is dependent on accurate timing of expression, as shown by analysis of EBA-GFP chimeric protein distribution in transgenic parasites.\",\n      \"method\": \"Transgenic EBA-GFP chimeric proteins; immunofluorescence localization; domain-swap analysis in P. falciparum\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic chimeric protein approach with localization readout, multiple EBL family members tested, single lab\",\n      \"pmids\": [\"16935855\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PfROM4 cleaved EBA-175 (along with TRAP, CTRP, MTRAP, PFF0800c, BAEBL, JESEBL, MAEBL, Rh1, Rh2a, Rh2b, Rh4) efficiently in a heterologous assay; cleavage was dependent on the adhesin transmembrane domains. Swapping transmembrane regions between BAEBL and AMA1 switched the cleavage preferences of PfROMs 1 and 4, confirming that the transmembrane domain determines substrate specificity.\",\n      \"method\": \"Heterologous rhomboid protease cleavage assay; transmembrane domain swap experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic cleavage assay with domain swaps establishing specificity determinants, single lab\",\n      \"pmids\": [\"17040128\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein disulfide isomerase PfPDI-8 facilitates disulfide-dependent conformational folding of EBA-175 in vitro, demonstrated by biochemical reconstitution showing PfPDI-8 is a potent oxido-reductase that assists in the proper folding of recombinant EBA-175.\",\n      \"method\": \"Biochemical oxido-reductase assay; in vitro protein folding reconstitution with recombinant PfPDI-8 and EBA-175\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution assay, single lab, single method\",\n      \"pmids\": [\"16806221\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Exposure of P. falciparum merozoites to low potassium ion concentrations (as in blood plasma) triggers a rise in cytosolic calcium via a phospholipase C-mediated pathway, which then drives secretion of EBA-175 from micronemes to the merozoite surface. Subsequently, EBA-175 interaction with its receptor glycophorin A restores basal cytosolic calcium levels and triggers rhoptry protein release.\",\n      \"method\": \"Time-lapse video microscopy of intracellular calcium in merozoites; flow cytometry for cytosolic calcium and surface expression of apical organelle proteins; pharmacological inhibition of phospholipase C\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, flow cytometry, pharmacological inhibition) dissecting sequential signal-triggered secretion, single lab\",\n      \"pmids\": [\"20140184\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EBA-175, EBA-181, and EBA-140 (EBL proteins) function cooperatively with PfRh (reticulocyte binding-like) proteins in erythrocyte invasion. Loss of EBA-181 function ablates antibody inhibition mediated by PfRh2a/b, and loss of some ebl genes results in upregulation of PfRh family transcripts, demonstrating functional interaction and compensatory regulation between the two families.\",\n      \"method\": \"Single and double gene knockouts (eba-175, eba-181, eba-140); invasion assays; antibody growth inhibition assays; transcriptional profiling\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple single and double knockout lines with defined functional and transcriptional phenotypes, mechanistic cross-family interaction established\",\n      \"pmids\": [\"21149582\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Structural basis for antibody inhibition of EBA-175 was established by X-ray crystallography and small-angle X-ray scattering. The potent inhibitory antibody R217 engages critical glycophorin A (GpA)-binding residues and the proposed dimer interface of EBA-175 RII, directly blocking GpA engagement. A weakly inhibitory antibody R218 binds an asparagine-rich surface loop and does not prevent GpA binding.\",\n      \"method\": \"X-ray crystallography of antibody-RII complexes; small-angle X-ray scattering; direct receptor binding assay; epitope mapping\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of two distinct antibody complexes combined with direct receptor binding assays and functional inhibition data in a single study\",\n      \"pmids\": [\"23717209\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The full ectodomain of EBA-175 (PfEBA175 FL) binds native glycophorin A with a KD of ~0.26 μM and can self-associate. The region II (RII) fragment alone bound glycophorin A with lower affinity, demonstrating that regions outside the DBL domains are important for GYPA interaction. Antibodies directed to non-DBL regions also contribute to invasion inhibition.\",\n      \"method\": \"Recombinant expression of full-length EBA-175 ectodomain; quantitative binding assay (SPR or equivalent); invasion inhibition with anti-non-DBL antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative binding assay comparing full-length vs domain fragment, with functional invasion inhibition, single lab\",\n      \"pmids\": [\"24043627\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EBA-175 interaction with glycophorin A triggers secretion of rhoptry protein PfTRAMP from rhoptries during erythrocyte invasion. Antibodies against PfTRAMP block invasion, and combination of anti-PfTRAMP and anti-EBA-175 antibodies shows additive invasion inhibition, placing EBA-175 upstream of rhoptry protein release in the invasion cascade.\",\n      \"method\": \"Localization studies (immunofluorescence); invasion inhibition assays with antibody combinations; functional dissection of secretion sequence\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis established through invasion sequence and antibody combination assays, single lab\",\n      \"pmids\": [\"23387921\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EBA-175 binding to glycophorin A on the erythrocyte surface triggers an increase in cytoskeletal tension and a reduction in the bending modulus of the red cell membrane. The reduction in bending modulus is directly correlated with parasite invasion efficiency, indicating EBA-175 primes the erythrocyte biophysically to facilitate invasion.\",\n      \"method\": \"Real-time deformability cytometry; flicker spectroscopy; quantitative correlation of membrane biophysical changes with invasion efficiency\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal biophysical methods with functional correlation, single lab\",\n      \"pmids\": [\"28373555\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EBA-175 binding to glycophorin A activates a phosphorylation cascade in erythrocyte cytoskeletal proteins that alters the viscoelastic properties of the host cell membrane, conditioning it for successful invasion. TRPM7 kinase inhibitors (FTY720 and waixenicin A) block this phosphorylation cascade, inhibiting the deformability change and merozoite invasion.\",\n      \"method\": \"Erythrocyte deformability assay; phosphoproteomics of EBA-175-treated erythrocytes; pharmacological inhibition of TRPM7 kinase; invasion inhibition assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic and functional pharmacological approaches, single lab, mechanistic pathway established\",\n      \"pmids\": [\"28226242\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Epigenetic repression of eba-175 using a CRISPR/dCas9 system fused to an epigenetic effector domain (erasing histone acetylation at the eba-175 transcription start site) significantly reduced EBA-175 expression and caused a switch in the parasite's invasion pathway, demonstrating that transcriptional regulation of eba-175 controls invasion pathway usage.\",\n      \"method\": \"CRISPR/dCas9 epigenetic editing (histone deacetylation at eba-175 TSS); RT-PCR/Western blot for expression; invasion pathway assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct epigenetic intervention with functional invasion pathway readout, single lab\",\n      \"pmids\": [\"30584102\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBA-175 interacts with the erythrocyte transmembrane protein CD44 and induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. P. falciparum invasion is reduced in CD44-null cultured red blood cells. The primary erythrocyte binding of EBA-175 relies on its canonical receptor glycophorin A, with CD44 acting as a coreceptor.\",\n      \"method\": \"CRISPR/Cas9 knockout of CD44 in primary human hematopoietic stem cells; ex vivo erythropoiesis; invasion assay; binding assay with receptor-deficient cells; phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout of host receptor combined with direct binding assay and phosphorylation readout, mechanistic dissection of primary vs coreceptor roles\",\n      \"pmids\": [\"37832027\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EBA-175 interacts with CD44 on erythrocytes and induces RBC membrane changes that increase accessibility of surface proteins including Basigin, and enhance binding of the PfRH5/PCRCR invasion complex to Basigin. These effects are similar to those of an anti-CD44 cross-linking antibody (BRIC 222), suggesting EBA-175 acts as a functional CD44 cross-linker to coordinate downstream invasion interactions.\",\n      \"method\": \"Recombinant EBA-175 treatment of RBCs; binding assay for PfRH5/PCRCR to Basigin; flow cytometry for surface protein accessibility; P. falciparum invasion assay with EBA-175 addition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with recombinant protein, single lab, mechanistic model supported by multiple orthogonal readouts\",\n      \"pmids\": [\"41354647\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Optical tweezer-based quantification showed that interventions disrupting EBA-175-like antigen (PfEBA) family function significantly reduced the force and frequency of merozoite-erythrocyte attachment. Deletion of EBA-175 (PfEBA175) had a significant impact on invasion under flow conditions but not in static culture, establishing PfEBA family proteins (including EBA-175) as central mediators of merozoite attachment.\",\n      \"method\": \"Optical tweezers direct force measurement of merozoite-erythrocyte attachment; genetically modified parasite lines; invasion assay under flow and static conditions\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel biophysical assay with genetic deletion, single lab, established contribution of EBA-175 to attachment force\",\n      \"pmids\": [\"39312588\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EBA-175 region II polymorphisms (high sequence variability between strains) do not affect the receptor specificity or the ability of EBA-175 to bind glycophorin A; unlike EBA-140 and EBA-181, EBA-175 shows no variability in its ability to bind its receptor despite high polymorphism in region II.\",\n      \"method\": \"Erythrocyte binding assays with recombinant region II variants; invasion assays with receptor-deficient erythrocytes\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with multiple allelic variants, single lab, clear negative result for receptor specificity change\",\n      \"pmids\": [\"19204093\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"EBA-175 (PF3D7_0731500) is a P. falciparum microneme protein that is secreted upon low-potassium/calcium signaling to the merozoite surface, where its region II (comprising tandem Duffy binding-like domains F1 and F2 arranged as a dimer) binds Neu5Ac(α2-3)Gal O-linked glycans on glycophorin A of human erythrocytes; this interaction drives biophysical changes (increased cytoskeletal tension, reduced membrane bending modulus) and a CD44-dependent phosphorylation cascade in the erythrocyte that together facilitate invasion, while EBA-175 itself is shed by PfROM4-mediated intramembrane cleavage of its transmembrane domain at around the time of invasion, with its cytoplasmic domain being essential for invasion function (though not for microneme targeting), and loss of EBA-175 function causes parasites to switch to sialic acid-independent invasion pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EBA-175 (PF3D7_0731500) is a Plasmodium falciparum merozoite microneme adhesin that mediates sialic acid-dependent erythrocyte recognition during blood-stage invasion [#0, #7]. Its erythrocyte-binding activity resides in the cysteine-rich region II (RII), which specifically engages the terminal Neu5Ac(\\u03b12-3)Gal sequences of O-linked glycans on glycophorin A, requiring both sialic acid and the glycophorin A peptide backbone [#3, #5]; RII adopts a two-domain (F1/F2) Duffy binding-like fold that dimerizes to create glycan-binding channels, with F2 making the majority of glycan contacts [#13], and full ectodomain contributions outside RII further support glycophorin A engagement [#22]. Receptor engagement is not merely adhesive: EBA-175 binding to glycophorin A, with CD44 acting as a coreceptor, drives erythrocyte cytoskeletal phosphorylation, increases cytoskeletal tension and lowers the membrane bending modulus, biophysically priming the red cell for invasion [#24, #25, #27], and functions upstream of downstream invasion signals including calcium restoration and rhoptry protein release [#19, #23]. Genetic disruption inactivates the EBA-175/glycophorin A route and, in strains such as W2mef, triggers a stable switch to sialic acid-independent invasion, defining EBA-175 as one interchangeable ligand within a redundant invasion-pathway network alongside the PfRh proteins [#7, #11, #20]. EBA-175 is secreted upon a low-potassium/phospholipase C/calcium signal, and is shed from the merozoite surface by the rhomboid protease PfROM4, which cleaves within its transmembrane domain around the time of invasion [#15, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing that a secreted parasite antigen could bridge merozoites and susceptible erythrocytes framed EBA-175 as a candidate invasion ligand rather than a passive surface protein.\",\n      \"evidence\": \"erythrocyte binding assays with culture supernatants and cross-strain invasion inhibition in vitro\",\n      \"pmids\": [\"3901257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular receptor not identified\", \"Binding domain within the protein not mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Camp, FCR-3\"}]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Cloning the single-ORF gene and demonstrating that a surface-exposed peptide region elicits invasion-blocking antibodies connected the protein sequence to functional invasion and binding.\",\n      \"evidence\": \"gene sequencing plus rabbit immunization with a synthetic peptide followed by invasion and binding inhibition assays\",\n      \"pmids\": [\"2229177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unresolved\", \"Precise binding domain not yet delimited\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Showing that a 190-kDa precursor is processed to 175 kDa and released at schizont rupture in a protease-dependent manner established that EBA-175 is proteolytically shed.\",\n      \"evidence\": \"biochemical fractionation, Western blot, and protease inhibitor treatment of schizont-infected erythrocytes\",\n      \"pmids\": [\"2194125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible protease not identified\", \"Cleavage site not mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defining Neu5Ac(\\u03b12-3)Gal on glycophorin A as the binding determinant identified the molecular receptor and its precise glycan linkage requirement.\",\n      \"evidence\": \"competitive oligosaccharide inhibition, co-immunoprecipitation with anti-glycophorin A, enzyme-modified erythrocyte binding, and influenza C esterase discrimination of Neu5Ac vs Neu5,9Ac2\",\n      \"pmids\": [\"1310320\", \"1565137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of the peptide backbone not yet quantified\", \"Binding domain within EBA-175 not localized\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping binding to the cysteine-rich region II and to glycophorin A (not B) localized the functional ligand domain and defined receptor specificity.\",\n      \"evidence\": \"expression of truncated constructs on COS cells and binding assays with glycophorin-variant and glycophorin-deficient erythrocytes\",\n      \"pmids\": [\"8009226\", \"8078523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of glycan recognition unknown\", \"Role of the glycophorin B ligand not attributable to EBA-175\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genetic disruption showed EBA-175 is functionally dispensable in some backgrounds because parasites switch to sialic acid-independent invasion, revealing invasion-pathway redundancy.\",\n      \"evidence\": \"targeted gene disruption in W2mef and Dd2/Nm with expression, localization, and sialic-acid-dependence invasion readouts\",\n      \"pmids\": [\"10861015\", \"10989151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the pathway switch not defined\", \"Compensating ligands not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"W2mef\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2/Nm\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Stage-specific transcription peaking late in schizogony and independent trafficking of EBA-175 relative to AMA1 clarified the timing and organellar logistics of the ligand's deployment.\",\n      \"evidence\": \"quantitative RT-PCR in synchronized parasites and parallel immunofluorescence/Western tracking of EBA-175 and AMA1 processing\",\n      \"pmids\": [\"12000842\", \"12228305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional regulators not identified\", \"Trafficking signal not yet mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Domain-swap and knockout experiments dissected functional domains: the cytoplasmic tail carries invasion-essential (but not trafficking) information and is interchangeable with TRAP, while the EBA-175/glycophorin A axis is the major chymotrypsin-resistant pathway.\",\n      \"evidence\": \"domain-swap transgenics with functional rescue and localization, plus knockout/truncation lines assayed against enzyme-treated erythrocytes across strains\",\n      \"pmids\": [\"12876279\", \"12672957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic-domain effector machinery not identified\", \"Strain-dependence of pathway switching unexplained\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"W2mef, 3D7\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The atomic structure of RII revealed a two-DBL-domain (F1/F2) monomer that dimerizes to form glycan-binding channels, providing the structural mechanism of sialylated-glycan recognition and its evolved preference for human Neu5Ac.\",\n      \"evidence\": \"X-ray crystallography of RII-glycan complex and comparative sialic-acid binding assays with P. falciparum and P. reichenowi orthologs\",\n      \"pmids\": [\"16051144\", \"16126901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full ectodomain-glycophorin A complex unresolved\", \"Coupling of binding to signaling not structurally defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium reichenowi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying PfROM4 as the intramembrane protease that cleaves the EBA-175 transmembrane domain, along with the cysteine-rich ectodomain microneme-targeting signal, resolved how EBA-175 is trafficked and shed and showed cleavage is essential for growth.\",\n      \"evidence\": \"heterologous rhomboid cleavage assays, transmembrane mutagenesis and domain swaps, EBA-GFP chimera localization, and in vitro folding with PfPDI-8\",\n      \"pmids\": [\"17000879\", \"16935855\", \"17040128\", \"16806221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo timing and regulation of shedding not fully resolved\", \"Functional requirement of PfPDI-8 folding in vivo not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking low-potassium/phospholipase-C/calcium signaling to EBA-175 secretion, and cooperative function with PfRh proteins, placed EBA-175 within an ordered, network-regulated invasion cascade.\",\n      \"evidence\": \"live calcium imaging, flow cytometry, PLC inhibition, and single/double ebl-PfRh knockouts with invasion and transcriptional profiling\",\n      \"pmids\": [\"20140184\", \"21149582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor coupling secretion to calcium not identified\", \"Mechanism of cross-family transcriptional compensation unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Antibody-complex structures, full-ectodomain binding quantification, and epistasis with PfTRAMP defined how inhibitory antibodies block glycophorin A engagement and positioned EBA-175 upstream of rhoptry release.\",\n      \"evidence\": \"crystallography and SAXS of RII-antibody complexes, SPR-type binding of full-length ectodomain, and invasion inhibition with antibody combinations\",\n      \"pmids\": [\"23717209\", \"24043627\", \"23387921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal relayed from receptor binding to rhoptry secretion not molecularly traced\", \"Role of non-DBL regions in vivo not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that EBA-175-glycophorin A engagement drives erythrocyte cytoskeletal phosphorylation and measurable biophysical changes reframed EBA-175 as an active signaling ligand that primes the host cell for invasion.\",\n      \"evidence\": \"deformability cytometry, flicker spectroscopy, phosphoproteomics, and TRPM7 kinase inhibition with invasion readouts\",\n      \"pmids\": [\"28373555\", \"28226242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Host receptor coupling the ligand to TRPM7 signaling not defined at this stage\", \"Causal chain from tension change to invasion not fully resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epigenetic silencing of eba-175 showed that transcriptional control of the ligand itself governs invasion-pathway usage, connecting gene regulation to phenotypic pathway switching.\",\n      \"evidence\": \"CRISPR/dCas9 epigenetic editing at the eba-175 TSS with expression and invasion-pathway assays\",\n      \"pmids\": [\"30584102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous epigenetic regulators not identified\", \"Trigger for physiological switching unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying CD44 as a coreceptor and showing EBA-175 acts as a CD44 cross-linker that increases Basigin accessibility for the PfRH5/PCRCR complex mechanistically linked EBA-175 binding to downstream invasion-complex engagement and to attachment force.\",\n      \"evidence\": \"CD44 knockout erythroid cells, recombinant EBA-175 treatment with Basigin/PfRH5 binding and surface-accessibility readouts, and optical-tweezer force measurements of attachment\",\n      \"pmids\": [\"37832027\", \"41354647\", \"39312588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of EBA-175-CD44 interaction unknown\", \"How glycophorin A and CD44 engagement are integrated not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How receptor engagement is mechanistically transduced into the erythrocyte signaling and membrane-remodeling events, and how the cytoplasmic-tail invasion machinery operates, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from glycophorin A/CD44 binding to the erythrocyte phosphorylation cascade not fully defined\", \"Effectors engaged by the EBA-175 cytoplasmic domain unidentified\", \"Integration of glycophorin A, CD44, and Basigin engagement into a single invasion mechanism unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [3, 5, 13, 4]},\n      {\"term_id\": \"GO:0033691\", \"supporting_discovery_ids\": [3, 5, 6, 22, 30]},\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [22, 23, 27, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [8, 9, 16]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [7, 9, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [0, 1, 5, 7, 11]},\n      {\"term_id\": \"GO:0046718\", \"supporting_discovery_ids\": [19, 23, 24, 25, 28, 29]}\n    ],\n    \"complexes\": [\n      \"EBA-175 region II forms a homodimer that creates glycan-binding channels [#13]\",\n      \"Full-length EBA-175 ectodomain can self-associate [#22]\"\n    ],\n    \"partners\": [\n      \"Glycophorin A (human erythrocyte receptor, Neu5Ac(\\u03b12-3)Gal glycans) [#3, #5, #6, #22]\",\n      \"CD44 (erythrocyte coreceptor / cross-linking target) [#27, #28]\",\n      \"PfROM4 (rhomboid intramembrane protease that cleaves the EBA-175 TM domain) [#15, #17]\",\n      \"PfPDI-8 (protein disulfide isomerase assisting EBA-175 folding in vitro) [#18]\",\n      \"PfRh family proteins (cooperative/compensatory invasion function) [#20]\",\n      \"PfTRAMP (rhoptry protein released downstream of EBA-175 engagement) [#23]\",\n      \"PfRH5/PCRCR complex and Basigin (accessibility enhanced by EBA-175-CD44 action) [#28]\"\n    ],\n    \"other_free_text\": [\n      \"EBA-175 binding to glycophorin A triggers erythrocyte cytoskeletal phosphorylation, increased cytoskeletal tension and reduced membrane bending modulus, priming the cell for invasion [#24, #25]\",\n      \"Secretion of EBA-175 from micronemes is triggered by low-potassium/phospholipase-C-mediated cytosolic calcium rise; receptor engagement then restores basal calcium and triggers rhoptry release [#19, #23]\",\n      \"Loss of EBA-175 function causes strain-dependent switching to sialic acid-independent invasion [#7, #11]\",\n      \"The cytoplasmic domain is essential for invasion function but dispensable for microneme trafficking, and is interchangeable with the TRAP cytoplasmic domain [#12]\",\n      \"Region II is highly polymorphic between strains, yet this polymorphism does not alter receptor specificity or glycophorin A binding [#30]\",\n      \"P. falciparum EBA-175 evolved to prefer human Neu5Ac over Neu5Gc, unlike the P. reichenowi ortholog [#14]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0731500","name":null,"product":"erythrocyte binding antigen-175","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"EBA175","evaluation":null}