{"gene":"PF3D7_0304600","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":1984,"finding":"The CSP gene of P. falciparum encodes a 412 amino acid protein containing 41 tandem tetrapeptide repeats (37× Asn-Ala-Asn-Pro and 4× Asn-Val-Asp-Pro), flanked by two conserved non-repeat regions (region I and region II) shared with P. knowlesi CS protein, suggesting these conserved regions may mediate binding to liver cells.","method":"Gene cloning and nucleotide sequence determination; monoclonal antibody inhibition with synthetic peptides","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — primary gene cloning and sequencing with functional antibody inhibition assay, foundational paper replicated by subsequent work","pmids":["6204383"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1984,"finding":"A cDNA clone encoding the P. falciparum CSP repeat region (PNANP tandem repeats) was isolated; the CS-beta-lactamase fusion protein specifically binds monoclonal antibodies to native CSP and inhibits their binding to native sporozoite CSP.","method":"cDNA library screening with monoclonal antibody; competitive binding inhibition assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cDNA cloning with functional antibody binding validation, independently corroborated by PMID 6204383","pmids":["6204384"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1985,"finding":"Recombinant CSP proteins composed of 16, 32, or 48 tandem copies of the NANP tetrapeptide repeat expressed in E. coli elicit antibodies in mice that react with native sporozoite CSP and block sporozoite invasion of human hepatoma cells in vitro, establishing the repeat region as sufficient for inducing invasion-blocking antibodies.","method":"Recombinant protein expression in E. coli; in vitro sporozoite invasion inhibition assay; mouse immunization","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro functional assay (sporozoite invasion inhibition) with recombinant protein, replicated across multiple constructs","pmids":["2988125"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1985,"finding":"Synthetic peptides from the NANP repeat region of P. falciparum CSP induce antibodies in mice and rabbits that recognize native CSP on sporozoites and block sporozoite invasion of human hepatoma cells in vitro; antibodies to region I and region II peptides had no invasion-blocking activity, though anti-region I antibodies recognized processed CSP by Western blot.","method":"Synthetic peptide immunization; sporozoite invasion inhibition assay; Western blot","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro functional invasion inhibition with defined peptides, multiple peptide regions tested with controls","pmids":["2988126"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1988,"finding":"P. berghei sporozoites undergoing gliding motility in vitro deposit trails of CSP corresponding to their movement patterns; CSP is released continuously as an exoantigen during motility, and anti-CSP antibodies inhibit sporozoite motility, suggesting CSP plays a direct role in gliding motility.","method":"Light microscopy with immunogold-silver staining (IGSS) using anti-CSP monoclonal antibody; motility inhibition by pre-treatment with inhibitory agents","journal":"The Journal of protozoology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-imaging observation of CSP trail deposition coupled with motility inhibition experiments, replicated in PMID 1787427","pmids":["3054075"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":1991,"finding":"CSP is released from the apical (leading) end of cytochalasin B-immobilized P. berghei sporozoites and translocated posteriorly along the surface via a cytochalasin-sensitive, apparently actin-mediated surface motor, providing a mechanistic model for the circumsporozoite precipitation (CSP) reaction and CS protein trail formation during gliding motility.","method":"Video microscopy and electron microscopy of cytochalasin B-immobilized sporozoites; immunolocalization of CSP","journal":"The Journal of protozoology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence (motility mechanism), two orthogonal microscopy methods, builds on PMID 3054075","pmids":["1787427"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":1993,"finding":"P. falciparum CSP binds to heparan sulfate proteoglycans (HSPGs) on the basolateral plasma membrane of hepatocytes via its region II-plus; binding is abolished by heparitinase treatment of hepatocytes; the CS-binding HSPGs from HepG2 cells have MW 400,000–700,000, are tightly membrane-associated, and share properties with the syndecan family.","method":"Heparitinase treatment of hepatocytes followed by CS binding assay; purification and partial characterization of HSPGs from HepG2 cells; trypsinization release assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical identification of receptor (HSPG) with enzymatic disruption control, HSPG purification, multiple orthogonal methods","pmids":["8478608"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1992,"finding":"Region II of P. falciparum, P. berghei, and P. vivax CSP specifically binds sulfatides and cholesterol-3-sulfate; this binding requires a disulfide bond between the two cysteines in region II (forming a small peptide loop); disruption of this disulfide (by reduction/alkylation) abolishes binding; sulfatide/cholesterol-3-sulfate recognition by region II is required during sporozoite invasion of liver cells, since dextran sulfate inhibits both CSP-sulfatide binding and P. berghei hepatocyte invasion.","method":"In vitro binding assay with recombinant CSP constructs (including region II deletion mutants); reduction/alkylation of disulfide bonds; dextran sulfate inhibition of sporozoite invasion of hepatocytes","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with domain deletion mutants and chemical disruption of disulfide, functional invasion inhibition assay","pmids":["1518521"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium vivax","strain":""}]},{"year":1996,"finding":"P. falciparum CSP interacts with both cell-surface heparan sulfate proteoglycans (HSPGs) and the low density lipoprotein receptor-related protein (LRP) on hepatocytes; binding of radiolabeled CSP to purified LRP occurs with Kd = 4.9 nM and is inhibited by receptor-associated protein (RAP); blockage of either LRP or HSPG alone reduces P. berghei invasion of hepatocytes by 60–70%, and combined blockage achieves ~65% inhibition; these two receptors represent the major mechanism for host cell invasion by sporozoites.","method":"Radiolabeled (125I) CSP binding to purified LRP; RAP and anti-LRP antibody blockade; heparinase treatment; invasion assays in LRP-deficient and HSPG-deficient cell lines","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative binding assay with Kd determination, multiple genetic and biochemical perturbation controls, invasion functional readout, orthogonal cell lines","pmids":["8920859"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":1998,"finding":"Native P. falciparum/P. berghei/P. vivax CSP translocated by sporozoites into host cell cytosol, as well as recombinant CSP introduced by liposome fusion or transfection, inhibits protein synthesis in mammalian cells; recombinant CSP associates with ribosomes (RNase-sensitive sites on rough microsomes); synthetic peptides of conserved region I and region II-plus displace CSP from rough microsomes (nanomolar Kd) and inhibit in vitro translation, suggesting CSP binds ribosomes to downregulate host protein synthesis.","method":"Liposome-mediated delivery and transient transfection of recombinant CSP; protein synthesis measurement; microsomal binding assay; synthetic peptide displacement assay; in vitro translation inhibition assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal delivery methods, biochemical fractionation, in vitro translation assay with synthetic peptide dissection; single lab","pmids":["9669999"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium vivax","strain":""}]},{"year":2001,"finding":"The amino terminus of P. falciparum CSP is essential for binding to liver cells and for inhibiting sporozoite invasion; deletion of as few as 6 amino acids from the N-terminus abolishes both binding activity and invasion inhibition; deletion of the TSR domain (region II) actually enhances binding 2–3-fold without losing receptor specificity but increases invasion inhibition, indicating the TSR domain is not the sole determinant of binding specificity.","method":"Eight truncated recombinant CSP constructs tested in liver cell binding assay and sporozoite invasion inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic deletion mutagenesis with direct binding and functional invasion assays, multiple constructs, single lab","pmids":["11751898"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"P. falciparum CSP functionally substitutes for P. berghei CSP in the rodent parasite; region I-deficient P. berghei sporozoites (carrying PfCSP lacking region I) show no impairment of motility, salivary gland invasion, or vertebrate host infection; region II-deficient sporozoites lose gliding motility and are severely impaired in mosquito salivary gland invasion and vertebrate host infection, establishing region II as essential for sporozoite motility and infectivity.","method":"Genetic replacement of P. berghei CSP gene with P. falciparum CSP gene and region I/II deletion variants; assessment of sporozoite motility, salivary gland invasion, and mouse infection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis by gene replacement, multiple phenotypic readouts (motility, salivary gland invasion, vertebrate infection), replicated across constructs","pmids":["12244064"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2007,"finding":"P. falciparum/P. berghei CSP contains a PEXEL/VTS motif that mediates its export into the hepatocyte cytoplasm, and a nuclear localization signal (NLS) that enables it to enter the hepatocyte nucleus; nuclear CSP outcompetes NFκB nuclear import, downregulating NFκB-controlled genes including those involved in inflammation; CSP also modulates expression of >1,000 host genes involved in diverse metabolic processes; CSP presence in the hepatocyte enhances parasite liver stage growth in vitro and in vivo.","method":"PEXEL/VTS motif identification and NLS identification; transfection/expression in hepatocytes; NFκB nuclear import competition assay; gene expression profiling; parasite growth measurement in vitro and in vivo","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal experiments (PEXEL/NLS identification, NFκB competition, transcriptomics, in vitro and in vivo parasite growth), single lab but high-impact journal with comprehensive mechanistic analysis","pmids":["17981117"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2009,"finding":"Recombinant P. falciparum CSP expressed in E. coli and Pichia pastoris forms highly extended, flexible, rod-like structures approximately 21–25 nm long and 1.5 nm wide as determined by dynamic light scattering, velocity sedimentation, and high-resolution atomic force microscopy; the protein is GPI-anchored; the TSR domain folds correctly as confirmed by conformation-dependent monoclonal antibodies that recognize live sporozoites and inhibit HepG2 cell invasion.","method":"Dynamic light scattering; velocity sedimentation; atomic force microscopy; in vitro sporozoite invasion inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods for structure characterization, functional validation of TSR domain folding by invasion inhibition, single lab","pmids":["19633296"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Crystal structures of the region III–TSR portion of P. falciparum CSP reveal that region III and the TSR domain fold together into a single structural unit called the 'αTSR' domain, which contains a hydrophobic pocket absent in typical TSR domains; polymorphic T-cell epitopes map to specialized αTSR regions; the N and C termini are unexpectedly close to each other; notably, the αTSR domain does not bind heparin, unlike the N-terminal region.","method":"X-ray crystallography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination (Tier 1 method), single lab","pmids":["22547819"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"A monoclonal antibody (mAb5D5) specific for the N-terminus of P. falciparum CSP inhibits proteolytic cleavage of CSP, which is a required step for sporozoite infection of hepatocytes; adoptive transfer of mAb5D5 strongly inhibits in vivo sporozoite infection in mice expressing PfCSP N-terminus, and protection is enhanced in combination with anti-repeat antibodies.","method":"Monoclonal antibody characterization; proteolytic cleavage assay; passive transfer in vivo infection assay in transgenic mouse model","journal":"The Journal of infectious diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mechanistic identification of proteolytic cleavage as a required infectivity step, functional in vivo passive transfer validation, combined with mechanistic in vitro cleavage assay","pmids":["25762791"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"Crystal structures of Fab fragments of two protective monoclonal antibodies (mAb311 and mAb317) bound to an (NPNA)3 peptide show that one to three NPNA repeats adopt well-defined type I β-turns; negative-stain electron microscopy of a recombinant shortened CSP saturated with Fabs reveals a compact CSP with multiple Fabs bound, forming a highly organized helical structure for the rsCSP-Fab311 complex.","method":"X-ray crystallography of Fab–peptide complexes; negative-stain electron microscopy of rsCSP–Fab complexes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures and EM structures in same study, two independent antibodies characterized, in vivo inhibition data (≥97%) corroborate functional relevance","pmids":["29138320"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"Cryo-EM structure (~3.4-Å) of recombinant shortened P. falciparum CSP bound to Fabs of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies; this unusual structure appears to be stabilized and/or induced by somatic mutations at inter-Fab contact residues (non-antigen-contact positions) that enhance adjacent Fab–Fab interactions.","method":"Cryo-electron microscopy structure determination (~3.4 Å); mutational analysis of inter-Fab contacts","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mutational validation of inter-Fab contacts, single lab","pmids":["30324137"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"Mosquito heparan sulfate isolated from Anopheles stephensi salivary glands and midguts contains the trisulfated disaccharide sequence found in human liver heparan sulfate (the CSP receptor), and whole-mosquito heparan sulfate binds to CSP in vitro, suggesting a role for CSP–HSPG interaction within the mosquito during infection and transmission.","method":"Heparan sulfate isolation from mosquito tissues; disaccharide microanalysis; in vitro binding of mosquito HSPG to CSP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biochemical binding demonstrated, single lab, functional consequence in mosquito not directly tested","pmids":["17597060"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"In dendritic cells (DCs), P. falciparum/P. berghei CSP epitopes are cross-presented to CD8+ T cells via an endosomal pathway requiring TAP transporters; in hepatocytes, CSP must be secreted directly into the cytosol and also uses TAP transporters to access the ER for MHC class I presentation; secretion of CSP into hepatocytes during liver stage infection is not dependent on the PEXEL/VTS export motifs in the protein.","method":"Transgenic parasite expressing mutant CSP (SIINFEKL insertion); endosomal pathway mutant mice (3d); cytochrome c treatment; TAP-deficient mice; in vivo T cell response assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mutant mouse strains and transgenic parasites used, orthogonal genetic perturbations (endosomal mutant, TAP-deficient), PEXEL/VTS mutant analysis","pmids":["21445239"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2018,"finding":"Anti-P. yoelii CSP repeat monoclonal antibody inhibits sporozoite motility and kills sporozoites in the host skin via a 'dotty death' phenotype that is complement- and Fc receptor γ-independent; cytotoxicity requires actomyosin motor-dependent translocation and stripping of the CSP surface coat, exposing the sporozoite membrane to the pore-forming-like protein SPECT; cognate anti-CSP repeat mAbs also kill P. berghei and P. falciparum sporozoites.","method":"Passive transfer of anti-CSP mAb in rodent model; intravital microscopy in skin; in vitro motility and cytotoxicity assays; complement/FcRγ-deficient mouse models","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological perturbations, intravital imaging, in vitro assays, cross-species validation","pmids":["30349082"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"P. berghei/P. falciparum CSP repeat region has elastic, spring-like biophysical properties: sporozoite mutants with truncated or scrambled CSP repeats exhibit impaired gliding motility due to altered adhesion site (containing TRAP) formation and dynamics; single-molecule fluorescence-force spectroscopy demonstrates the repeats behave as a stiff linear spring whose elasticity depends on repeat length and is lost when repeats are scrambled; CSP coat integrity affects the assembly of TRAP-containing adhesion sites.","method":"CSP repeat truncation and scramble mutant parasites; gliding motility assays; single-molecule fluorescence-force spectroscopy; adhesion site imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biophysical measurement (single-molecule force spectroscopy) combined with genetic mutants and functional motility assays, multiple orthogonal methods","pmids":["40983687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":1990,"finding":"A 16-amino acid epitope from the P. yoelii CSP is recognized by CD8+ cytotoxic T cells from immune mice; lymphocytes stimulated with this peptide kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner, demonstrating that CSP epitopes are presented on the surface of infected hepatocytes and can be targets for protective CTL even though intact CSP has not been detected on the hepatocyte surface.","method":"In vitro CTL killing assay with peptide-stimulated lymphocytes; MHC restriction confirmed","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional CTL killing assay with MHC restriction control, liver stage parasites as targets","pmids":["1689762"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2007,"finding":"P. berghei-infected primary hepatocytes process and present CSP-derived peptides to specific CD8+ T cells via a pathway involving the proteasome, antigen transport through a post-ER compartment, and aspartic proteases; both infected and traversed (but not productively infected) hepatocytes can present CSP epitopes in the context of H-2Kd MHC class I molecules.","method":"Primary hepatocyte infection with wild-type and spect−/− P. berghei sporozoites; proteasome inhibitors; protease inhibitors; CD8+ T cell activation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (spect−/− parasites) and pharmacological dissection of antigen processing pathway, multiple inhibitors, functional T cell readout","pmids":["17513754"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"finding":"Anti-P. berghei CSP monoclonal antibody 3D11 neutralizes sporozoites in the liver through a sequential late-killing mechanism: it first inhibits sporozoite motility and sinusoidal extravasation, then blocks hepatocyte invasion, and ultimately kills parasites inside invaded cells over several hours; bioluminescence imaging showed accumulation of 3D11 effects was necessary to eliminate liver parasites.","method":"Intravital microscopy; bioluminescence imaging in rodent malaria model; passive transfer of mAb 3D11","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vivo imaging with defined mechanistic sequence, single lab, single antibody studied","pmids":["39951341"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"P. falciparum CSP is a GPI-anchored, highly extended rod-like protein (~21–25 nm) that densely coats the sporozoite surface; its NANP central repeat region has elastic spring-like biophysical properties required for TRAP-containing adhesion site assembly and gliding motility; the conserved region II (containing a disulfide-bonded loop) mediates binding to heparan sulfate proteoglycans and LRP on hepatocytes (and mosquito tissues) as well as to sulfatides/cholesterol-3-sulfate, while the N-terminus is essential for liver cell binding; region III and the TSR domain fold together into a single αTSR domain; during sporozoite gliding, CSP is released apically and translocated posteriorly by the actomyosin motor; anti-CSP repeat antibodies can kill sporozoites in the skin by stripping the CSP coat and exposing the membrane to SPECT; after sporozoite invasion of hepatocytes, CSP is exported via its PEXEL/VTS motif into the hepatocyte cytosol and nucleus (via its NLS) where it outcompetes NFκB nuclear import, suppresses inflammatory gene expression, and modulates host metabolism to promote liver stage parasite growth; CSP is also processed and presented on hepatocyte MHC class I molecules to CD8+ T cells via a proteasome-, TAP-, and aspartic-protease-dependent pathway, and proteolytic cleavage of CSP at its N-terminus is a required step for sporozoite infectivity of hepatocytes."},"narrative":{"mechanistic_narrative":"PF3D7_0304600 encodes the circumsporozoite protein (CSP), a GPI-anchored surface coat protein that densely covers the Plasmodium sporozoite and governs its motility, hepatocyte targeting, and immune interface [PMID:6204383, PMID:19633296]. The protein is organized into an N-terminal conserved region, a central tandem repeat region (predominantly NANP tetrapeptides), and a C-terminal conserved region II shared across Plasmodium species [PMID:6204383, PMID:6204384]. The central NANP repeat is highly extended and behaves as an elastic, spring-like element whose length-dependent stiffness is required for proper assembly and dynamics of TRAP-containing adhesion sites that drive gliding motility [PMID:19633296, PMID:40983687]; consistent with this motile role, CSP is released apically and translocated posteriorly along the sporozoite surface by an actomyosin-based motor, depositing trails during gliding [PMID:3054075, PMID:1787427]. Host cell targeting is mediated at multiple sites: conserved region II binds heparan sulfate proteoglycans, the LDL-receptor-related protein LRP, and sulfatides/cholesterol-3-sulfate via a disulfide-bonded loop, and is essential for sporozoite motility and infectivity [PMID:8478608, PMID:1518521, PMID:8920859, PMID:12244064], while the N-terminus is independently required for liver-cell binding and its proteolytic cleavage is a prerequisite for hepatocyte infection [PMID:11751898, PMID:25762791]. Structurally, region III and the TSR domain fold into a single αTSR domain, and the repeat region adopts type I β-turns that can be organized into spiral/helical arrays by protective antibodies [PMID:22547819, PMID:29138320, PMID:30324137]. After invasion, CSP is exported into the hepatocyte cytosol and nucleus, where it outcompetes NFκB nuclear import to suppress inflammatory gene expression and reprograms host metabolic genes to favor liver-stage growth, and can inhibit host protein synthesis through ribosome association [PMID:9669999, PMID:17981117]. CSP-derived peptides are processed and presented on hepatocyte MHC class I to CD8+ T cells, and anti-repeat antibodies neutralize sporozoites in the skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT [PMID:30349082, PMID:1689762, PMID:17513754, PMID:39951341].","teleology":[{"year":1984,"claim":"Establishing the primary structure of CSP defined its modular architecture and pointed to the conserved flanking regions as candidate liver-cell binding determinants.","evidence":"Gene cloning and sequencing with monoclonal antibody peptide inhibition in P. falciparum","pmids":["6204383","6204384"],"confidence":"High","gaps":["Function of the conserved regions not yet tested experimentally","Repeat region role in motility unknown at this stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1985,"claim":"Demonstrating that the NANP repeat alone elicits invasion-blocking antibodies identified the repeat as the dominant protective B-cell epitope and vaccine target.","evidence":"Recombinant and synthetic-peptide immunization with in vitro sporozoite invasion inhibition of hepatoma cells","pmids":["2988125","2988126"],"confidence":"High","gaps":["Mechanism by which anti-repeat antibodies block invasion not defined","Role of region I and II antibodies unclear beyond lacking invasion inhibition"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1991,"claim":"Live imaging showed CSP is deposited as trails and translocated apical-to-posterior by an actin-dependent surface motor, linking CSP directly to gliding motility.","evidence":"Immunolocalization and video/electron microscopy of cytochalasin B-immobilized P. berghei sporozoites; motility inhibition by anti-CSP","pmids":["3054075","1787427"],"confidence":"High","gaps":["Molecular connection between CSP and the motor/adhesin machinery not resolved","Shown in P. berghei only"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":1996,"claim":"Biochemical identification of hepatocyte receptors defined the molecular basis of CSP-mediated host cell targeting.","evidence":"Disulfide-dependent region II binding to sulfatides/cholesterol-3-sulfate, HSPG binding via region II-plus, and quantitative LRP binding with invasion assays in P. falciparum/P. berghei","pmids":["1518521","8478608","8920859"],"confidence":"High","gaps":["Relative in vivo contribution of each receptor not fully resolved","Whether receptor engagement precedes or follows N-terminal cleavage unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium vivax","strain":""}]},{"year":2002,"claim":"Genetic dissection assigned distinct in vivo roles to the conserved regions, establishing region II as essential for motility and infectivity.","evidence":"Gene replacement of P. berghei CSP with PfCSP region I/II deletion variants and phenotyping of motility, salivary gland invasion, and mouse infection","pmids":["12244064"],"confidence":"High","gaps":["Region I dispensability in this system leaves its molecular role open","Mechanism by which region II supports motility not defined"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2001,"claim":"Deletion mapping showed the N-terminus is essential for liver-cell binding independently of the TSR domain, distributing binding function across the protein.","evidence":"Systematic truncation of recombinant PfCSP tested in liver-cell binding and invasion inhibition assays","pmids":["11751898"],"confidence":"High","gaps":["N-terminal receptor identity not determined","Interplay between N-terminal and region II binding sites unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"Discovery of a PEXEL/VTS and NLS in CSP revealed a post-invasion effector function in which CSP reprograms the hepatocyte to favor parasite growth.","evidence":"Motif identification, hepatocyte expression, NFκB nuclear import competition, transcriptional profiling, and parasite growth assays in P. falciparum/P. berghei","pmids":["17981117","9669999"],"confidence":"High","gaps":["Direct binding partners in the host nucleus not identified","Ribosome-association mechanism single-lab and mechanistically incomplete"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2011,"claim":"Antigen-processing studies defined how CSP epitopes reach MHC class I in hepatocytes and dendritic cells, clarifying the basis of protective CD8+ T-cell responses.","evidence":"Transgenic parasites, TAP-deficient and endosomal-mutant mice, proteasome/protease inhibitors, and CTL assays across P. yoelii/P. berghei/P. falciparum","pmids":["21445239","17513754","1689762"],"confidence":"High","gaps":["Identity of the aspartic protease processing CSP not defined","PEXEL-independence of CSP secretion into hepatocytes not mechanistically explained"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium yoelii","strain":""}]},{"year":2013,"claim":"Biophysical and crystallographic work resolved the overall shape and domain organization of CSP, defining the extended rod and the composite αTSR domain.","evidence":"DLS, sedimentation, AFM of recombinant PfCSP and X-ray structure of the region III–TSR unit","pmids":["19633296","22547819"],"confidence":"High","gaps":["Full-length structure including the repeat region not solved","Ligand for the αTSR hydrophobic pocket unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Blocking N-terminal proteolytic cleavage with a monoclonal antibody established that CSP processing is a required step for hepatocyte infection and a distinct protective target.","evidence":"mAb5D5 cleavage-inhibition assays and passive transfer in transgenic mice expressing the PfCSP N-terminus","pmids":["25762791"],"confidence":"High","gaps":["Protease responsible for cleavage not identified","Functional consequence of cleavage for downstream events undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Structures of protective antibodies bound to the repeats revealed defined β-turn conformations and antibody-organized spiral arrays, explaining the potency of anti-repeat neutralization.","evidence":"X-ray of Fab–(NPNA) complexes, negative-stain EM, and ~3.4-Å cryo-EM of rsCSP–Fab complexes with inter-Fab mutational analysis","pmids":["29138320","30324137"],"confidence":"High","gaps":["Conformation of the repeat on the native sporozoite surface not directly observed","In vivo relevance of Fab–Fab-stabilized arrays not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Mechanistic dissection of antibody killing showed anti-repeat mAbs neutralize sporozoites in skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT.","evidence":"Intravital microscopy, passive transfer, and complement/FcRγ-deficient models across P. yoelii/P. berghei/P. falciparum, with bioluminescence-tracked late killing in P. berghei","pmids":["30349082","39951341"],"confidence":"Medium","gaps":["Late intracellular killing mechanism studied with a single antibody in P. berghei","How coat stripping mechanistically engages SPECT not fully defined"],"attribution":[{"species":"Plasmodium yoelii","strain":""},{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Single-molecule force measurements established that the CSP repeat acts as an elastic spring whose length-dependent stiffness is required for TRAP-containing adhesion site assembly and gliding motility.","evidence":"Repeat truncation/scramble mutants, gliding assays, adhesion-site imaging, and single-molecule fluorescence-force spectroscopy in P. berghei/P. falciparum","pmids":["40983687"],"confidence":"High","gaps":["Direct physical link between the CSP spring and TRAP not resolved","Whether repeat elasticity influences receptor binding untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The identities of the N-terminal receptor and the protease that cleaves the CSP N-terminus, and the direct host nuclear/ribosomal partners of exported CSP, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["N-terminal hepatocyte receptor unidentified","Cleavage protease unidentified","Direct host-factor targets of nuclear CSP not defined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["CSP–TRAP-containing adhesion site (functional association) [#21]","recombinant shortened CSP–Fab 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II) shared with P. knowlesi CS protein, suggesting these conserved regions may mediate binding to liver cells.\",\n      \"method\": \"Gene cloning and nucleotide sequence determination; monoclonal antibody inhibition with synthetic peptides\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — primary gene cloning and sequencing with functional antibody inhibition assay, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"6204383\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"A cDNA clone encoding the P. falciparum CSP repeat region (PNANP tandem repeats) was isolated; the CS-beta-lactamase fusion protein specifically binds monoclonal antibodies to native CSP and inhibits their binding to native sporozoite CSP.\",\n      \"method\": \"cDNA library screening with monoclonal antibody; competitive binding inhibition assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cDNA cloning with functional antibody binding validation, independently corroborated by PMID 6204383\",\n      \"pmids\": [\"6204384\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Recombinant CSP proteins composed of 16, 32, or 48 tandem copies of the NANP tetrapeptide repeat expressed in E. coli elicit antibodies in mice that react with native sporozoite CSP and block sporozoite invasion of human hepatoma cells in vitro, establishing the repeat region as sufficient for inducing invasion-blocking antibodies.\",\n      \"method\": \"Recombinant protein expression in E. coli; in vitro sporozoite invasion inhibition assay; mouse immunization\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro functional assay (sporozoite invasion inhibition) with recombinant protein, replicated across multiple constructs\",\n      \"pmids\": [\"2988125\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Synthetic peptides from the NANP repeat region of P. falciparum CSP induce antibodies in mice and rabbits that recognize native CSP on sporozoites and block sporozoite invasion of human hepatoma cells in vitro; antibodies to region I and region II peptides had no invasion-blocking activity, though anti-region I antibodies recognized processed CSP by Western blot.\",\n      \"method\": \"Synthetic peptide immunization; sporozoite invasion inhibition assay; Western blot\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro functional invasion inhibition with defined peptides, multiple peptide regions tested with controls\",\n      \"pmids\": [\"2988126\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"P. berghei sporozoites undergoing gliding motility in vitro deposit trails of CSP corresponding to their movement patterns; CSP is released continuously as an exoantigen during motility, and anti-CSP antibodies inhibit sporozoite motility, suggesting CSP plays a direct role in gliding motility.\",\n      \"method\": \"Light microscopy with immunogold-silver staining (IGSS) using anti-CSP monoclonal antibody; motility inhibition by pre-treatment with inhibitory agents\",\n      \"journal\": \"The Journal of protozoology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-imaging observation of CSP trail deposition coupled with motility inhibition experiments, replicated in PMID 1787427\",\n      \"pmids\": [\"3054075\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CSP is released from the apical (leading) end of cytochalasin B-immobilized P. berghei sporozoites and translocated posteriorly along the surface via a cytochalasin-sensitive, apparently actin-mediated surface motor, providing a mechanistic model for the circumsporozoite precipitation (CSP) reaction and CS protein trail formation during gliding motility.\",\n      \"method\": \"Video microscopy and electron microscopy of cytochalasin B-immobilized sporozoites; immunolocalization of CSP\",\n      \"journal\": \"The Journal of protozoology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence (motility mechanism), two orthogonal microscopy methods, builds on PMID 3054075\",\n      \"pmids\": [\"1787427\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"P. falciparum CSP binds to heparan sulfate proteoglycans (HSPGs) on the basolateral plasma membrane of hepatocytes via its region II-plus; binding is abolished by heparitinase treatment of hepatocytes; the CS-binding HSPGs from HepG2 cells have MW 400,000–700,000, are tightly membrane-associated, and share properties with the syndecan family.\",\n      \"method\": \"Heparitinase treatment of hepatocytes followed by CS binding assay; purification and partial characterization of HSPGs from HepG2 cells; trypsinization release assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical identification of receptor (HSPG) with enzymatic disruption control, HSPG purification, multiple orthogonal methods\",\n      \"pmids\": [\"8478608\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Region II of P. falciparum, P. berghei, and P. vivax CSP specifically binds sulfatides and cholesterol-3-sulfate; this binding requires a disulfide bond between the two cysteines in region II (forming a small peptide loop); disruption of this disulfide (by reduction/alkylation) abolishes binding; sulfatide/cholesterol-3-sulfate recognition by region II is required during sporozoite invasion of liver cells, since dextran sulfate inhibits both CSP-sulfatide binding and P. berghei hepatocyte invasion.\",\n      \"method\": \"In vitro binding assay with recombinant CSP constructs (including region II deletion mutants); reduction/alkylation of disulfide bonds; dextran sulfate inhibition of sporozoite invasion of hepatocytes\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with domain deletion mutants and chemical disruption of disulfide, functional invasion inhibition assay\",\n      \"pmids\": [\"1518521\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"P. falciparum CSP interacts with both cell-surface heparan sulfate proteoglycans (HSPGs) and the low density lipoprotein receptor-related protein (LRP) on hepatocytes; binding of radiolabeled CSP to purified LRP occurs with Kd = 4.9 nM and is inhibited by receptor-associated protein (RAP); blockage of either LRP or HSPG alone reduces P. berghei invasion of hepatocytes by 60–70%, and combined blockage achieves ~65% inhibition; these two receptors represent the major mechanism for host cell invasion by sporozoites.\",\n      \"method\": \"Radiolabeled (125I) CSP binding to purified LRP; RAP and anti-LRP antibody blockade; heparinase treatment; invasion assays in LRP-deficient and HSPG-deficient cell lines\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative binding assay with Kd determination, multiple genetic and biochemical perturbation controls, invasion functional readout, orthogonal cell lines\",\n      \"pmids\": [\"8920859\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Native P. falciparum/P. berghei/P. vivax CSP translocated by sporozoites into host cell cytosol, as well as recombinant CSP introduced by liposome fusion or transfection, inhibits protein synthesis in mammalian cells; recombinant CSP associates with ribosomes (RNase-sensitive sites on rough microsomes); synthetic peptides of conserved region I and region II-plus displace CSP from rough microsomes (nanomolar Kd) and inhibit in vitro translation, suggesting CSP binds ribosomes to downregulate host protein synthesis.\",\n      \"method\": \"Liposome-mediated delivery and transient transfection of recombinant CSP; protein synthesis measurement; microsomal binding assay; synthetic peptide displacement assay; in vitro translation inhibition assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal delivery methods, biochemical fractionation, in vitro translation assay with synthetic peptide dissection; single lab\",\n      \"pmids\": [\"9669999\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The amino terminus of P. falciparum CSP is essential for binding to liver cells and for inhibiting sporozoite invasion; deletion of as few as 6 amino acids from the N-terminus abolishes both binding activity and invasion inhibition; deletion of the TSR domain (region II) actually enhances binding 2–3-fold without losing receptor specificity but increases invasion inhibition, indicating the TSR domain is not the sole determinant of binding specificity.\",\n      \"method\": \"Eight truncated recombinant CSP constructs tested in liver cell binding assay and sporozoite invasion inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic deletion mutagenesis with direct binding and functional invasion assays, multiple constructs, single lab\",\n      \"pmids\": [\"11751898\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"P. falciparum CSP functionally substitutes for P. berghei CSP in the rodent parasite; region I-deficient P. berghei sporozoites (carrying PfCSP lacking region I) show no impairment of motility, salivary gland invasion, or vertebrate host infection; region II-deficient sporozoites lose gliding motility and are severely impaired in mosquito salivary gland invasion and vertebrate host infection, establishing region II as essential for sporozoite motility and infectivity.\",\n      \"method\": \"Genetic replacement of P. berghei CSP gene with P. falciparum CSP gene and region I/II deletion variants; assessment of sporozoite motility, salivary gland invasion, and mouse infection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis by gene replacement, multiple phenotypic readouts (motility, salivary gland invasion, vertebrate infection), replicated across constructs\",\n      \"pmids\": [\"12244064\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"P. falciparum/P. berghei CSP contains a PEXEL/VTS motif that mediates its export into the hepatocyte cytoplasm, and a nuclear localization signal (NLS) that enables it to enter the hepatocyte nucleus; nuclear CSP outcompetes NFκB nuclear import, downregulating NFκB-controlled genes including those involved in inflammation; CSP also modulates expression of >1,000 host genes involved in diverse metabolic processes; CSP presence in the hepatocyte enhances parasite liver stage growth in vitro and in vivo.\",\n      \"method\": \"PEXEL/VTS motif identification and NLS identification; transfection/expression in hepatocytes; NFκB nuclear import competition assay; gene expression profiling; parasite growth measurement in vitro and in vivo\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal experiments (PEXEL/NLS identification, NFκB competition, transcriptomics, in vitro and in vivo parasite growth), single lab but high-impact journal with comprehensive mechanistic analysis\",\n      \"pmids\": [\"17981117\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant P. falciparum CSP expressed in E. coli and Pichia pastoris forms highly extended, flexible, rod-like structures approximately 21–25 nm long and 1.5 nm wide as determined by dynamic light scattering, velocity sedimentation, and high-resolution atomic force microscopy; the protein is GPI-anchored; the TSR domain folds correctly as confirmed by conformation-dependent monoclonal antibodies that recognize live sporozoites and inhibit HepG2 cell invasion.\",\n      \"method\": \"Dynamic light scattering; velocity sedimentation; atomic force microscopy; in vitro sporozoite invasion inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods for structure characterization, functional validation of TSR domain folding by invasion inhibition, single lab\",\n      \"pmids\": [\"19633296\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of the region III–TSR portion of P. falciparum CSP reveal that region III and the TSR domain fold together into a single structural unit called the 'αTSR' domain, which contains a hydrophobic pocket absent in typical TSR domains; polymorphic T-cell epitopes map to specialized αTSR regions; the N and C termini are unexpectedly close to each other; notably, the αTSR domain does not bind heparin, unlike the N-terminal region.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination (Tier 1 method), single lab\",\n      \"pmids\": [\"22547819\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A monoclonal antibody (mAb5D5) specific for the N-terminus of P. falciparum CSP inhibits proteolytic cleavage of CSP, which is a required step for sporozoite infection of hepatocytes; adoptive transfer of mAb5D5 strongly inhibits in vivo sporozoite infection in mice expressing PfCSP N-terminus, and protection is enhanced in combination with anti-repeat antibodies.\",\n      \"method\": \"Monoclonal antibody characterization; proteolytic cleavage assay; passive transfer in vivo infection assay in transgenic mouse model\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mechanistic identification of proteolytic cleavage as a required infectivity step, functional in vivo passive transfer validation, combined with mechanistic in vitro cleavage assay\",\n      \"pmids\": [\"25762791\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of Fab fragments of two protective monoclonal antibodies (mAb311 and mAb317) bound to an (NPNA)3 peptide show that one to three NPNA repeats adopt well-defined type I β-turns; negative-stain electron microscopy of a recombinant shortened CSP saturated with Fabs reveals a compact CSP with multiple Fabs bound, forming a highly organized helical structure for the rsCSP-Fab311 complex.\",\n      \"method\": \"X-ray crystallography of Fab–peptide complexes; negative-stain electron microscopy of rsCSP–Fab complexes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures and EM structures in same study, two independent antibodies characterized, in vivo inhibition data (≥97%) corroborate functional relevance\",\n      \"pmids\": [\"29138320\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure (~3.4-Å) of recombinant shortened P. falciparum CSP bound to Fabs of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies; this unusual structure appears to be stabilized and/or induced by somatic mutations at inter-Fab contact residues (non-antigen-contact positions) that enhance adjacent Fab–Fab interactions.\",\n      \"method\": \"Cryo-electron microscopy structure determination (~3.4 Å); mutational analysis of inter-Fab contacts\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mutational validation of inter-Fab contacts, single lab\",\n      \"pmids\": [\"30324137\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mosquito heparan sulfate isolated from Anopheles stephensi salivary glands and midguts contains the trisulfated disaccharide sequence found in human liver heparan sulfate (the CSP receptor), and whole-mosquito heparan sulfate binds to CSP in vitro, suggesting a role for CSP–HSPG interaction within the mosquito during infection and transmission.\",\n      \"method\": \"Heparan sulfate isolation from mosquito tissues; disaccharide microanalysis; in vitro binding of mosquito HSPG to CSP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biochemical binding demonstrated, single lab, functional consequence in mosquito not directly tested\",\n      \"pmids\": [\"17597060\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In dendritic cells (DCs), P. falciparum/P. berghei CSP epitopes are cross-presented to CD8+ T cells via an endosomal pathway requiring TAP transporters; in hepatocytes, CSP must be secreted directly into the cytosol and also uses TAP transporters to access the ER for MHC class I presentation; secretion of CSP into hepatocytes during liver stage infection is not dependent on the PEXEL/VTS export motifs in the protein.\",\n      \"method\": \"Transgenic parasite expressing mutant CSP (SIINFEKL insertion); endosomal pathway mutant mice (3d); cytochrome c treatment; TAP-deficient mice; in vivo T cell response assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mutant mouse strains and transgenic parasites used, orthogonal genetic perturbations (endosomal mutant, TAP-deficient), PEXEL/VTS mutant analysis\",\n      \"pmids\": [\"21445239\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Anti-P. yoelii CSP repeat monoclonal antibody inhibits sporozoite motility and kills sporozoites in the host skin via a 'dotty death' phenotype that is complement- and Fc receptor γ-independent; cytotoxicity requires actomyosin motor-dependent translocation and stripping of the CSP surface coat, exposing the sporozoite membrane to the pore-forming-like protein SPECT; cognate anti-CSP repeat mAbs also kill P. berghei and P. falciparum sporozoites.\",\n      \"method\": \"Passive transfer of anti-CSP mAb in rodent model; intravital microscopy in skin; in vitro motility and cytotoxicity assays; complement/FcRγ-deficient mouse models\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological perturbations, intravital imaging, in vitro assays, cross-species validation\",\n      \"pmids\": [\"30349082\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"P. berghei/P. falciparum CSP repeat region has elastic, spring-like biophysical properties: sporozoite mutants with truncated or scrambled CSP repeats exhibit impaired gliding motility due to altered adhesion site (containing TRAP) formation and dynamics; single-molecule fluorescence-force spectroscopy demonstrates the repeats behave as a stiff linear spring whose elasticity depends on repeat length and is lost when repeats are scrambled; CSP coat integrity affects the assembly of TRAP-containing adhesion sites.\",\n      \"method\": \"CSP repeat truncation and scramble mutant parasites; gliding motility assays; single-molecule fluorescence-force spectroscopy; adhesion site imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biophysical measurement (single-molecule force spectroscopy) combined with genetic mutants and functional motility assays, multiple orthogonal methods\",\n      \"pmids\": [\"40983687\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"A 16-amino acid epitope from the P. yoelii CSP is recognized by CD8+ cytotoxic T cells from immune mice; lymphocytes stimulated with this peptide kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner, demonstrating that CSP epitopes are presented on the surface of infected hepatocytes and can be targets for protective CTL even though intact CSP has not been detected on the hepatocyte surface.\",\n      \"method\": \"In vitro CTL killing assay with peptide-stimulated lymphocytes; MHC restriction confirmed\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional CTL killing assay with MHC restriction control, liver stage parasites as targets\",\n      \"pmids\": [\"1689762\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"P. berghei-infected primary hepatocytes process and present CSP-derived peptides to specific CD8+ T cells via a pathway involving the proteasome, antigen transport through a post-ER compartment, and aspartic proteases; both infected and traversed (but not productively infected) hepatocytes can present CSP epitopes in the context of H-2Kd MHC class I molecules.\",\n      \"method\": \"Primary hepatocyte infection with wild-type and spect−/− P. berghei sporozoites; proteasome inhibitors; protease inhibitors; CD8+ T cell activation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (spect−/− parasites) and pharmacological dissection of antigen processing pathway, multiple inhibitors, functional T cell readout\",\n      \"pmids\": [\"17513754\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Anti-P. berghei CSP monoclonal antibody 3D11 neutralizes sporozoites in the liver through a sequential late-killing mechanism: it first inhibits sporozoite motility and sinusoidal extravasation, then blocks hepatocyte invasion, and ultimately kills parasites inside invaded cells over several hours; bioluminescence imaging showed accumulation of 3D11 effects was necessary to eliminate liver parasites.\",\n      \"method\": \"Intravital microscopy; bioluminescence imaging in rodent malaria model; passive transfer of mAb 3D11\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vivo imaging with defined mechanistic sequence, single lab, single antibody studied\",\n      \"pmids\": [\"39951341\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum CSP is a GPI-anchored, highly extended rod-like protein (~21–25 nm) that densely coats the sporozoite surface; its NANP central repeat region has elastic spring-like biophysical properties required for TRAP-containing adhesion site assembly and gliding motility; the conserved region II (containing a disulfide-bonded loop) mediates binding to heparan sulfate proteoglycans and LRP on hepatocytes (and mosquito tissues) as well as to sulfatides/cholesterol-3-sulfate, while the N-terminus is essential for liver cell binding; region III and the TSR domain fold together into a single αTSR domain; during sporozoite gliding, CSP is released apically and translocated posteriorly by the actomyosin motor; anti-CSP repeat antibodies can kill sporozoites in the skin by stripping the CSP coat and exposing the membrane to SPECT; after sporozoite invasion of hepatocytes, CSP is exported via its PEXEL/VTS motif into the hepatocyte cytosol and nucleus (via its NLS) where it outcompetes NFκB nuclear import, suppresses inflammatory gene expression, and modulates host metabolism to promote liver stage parasite growth; CSP is also processed and presented on hepatocyte MHC class I molecules to CD8+ T cells via a proteasome-, TAP-, and aspartic-protease-dependent pathway, and proteolytic cleavage of CSP at its N-terminus is a required step for sporozoite infectivity of hepatocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0304600 encodes the circumsporozoite protein (CSP), a GPI-anchored surface coat protein that densely covers the Plasmodium sporozoite and governs its motility, hepatocyte targeting, and immune interface [#0, #13]. The protein is organized into an N-terminal conserved region, a central tandem repeat region (predominantly NANP tetrapeptides), and a C-terminal conserved region II shared across Plasmodium species [#0, #1]. The central NANP repeat is highly extended and behaves as an elastic, spring-like element whose length-dependent stiffness is required for proper assembly and dynamics of TRAP-containing adhesion sites that drive gliding motility [#13, #21]; consistent with this motile role, CSP is released apically and translocated posteriorly along the sporozoite surface by an actomyosin-based motor, depositing trails during gliding [#4, #5]. Host cell targeting is mediated at multiple sites: conserved region II binds heparan sulfate proteoglycans, the LDL-receptor-related protein LRP, and sulfatides/cholesterol-3-sulfate via a disulfide-bonded loop, and is essential for sporozoite motility and infectivity [#6, #7, #8, #11], while the N-terminus is independently required for liver-cell binding and its proteolytic cleavage is a prerequisite for hepatocyte infection [#10, #15]. Structurally, region III and the TSR domain fold into a single \\u03b1TSR domain, and the repeat region adopts type I \\u03b2-turns that can be organized into spiral/helical arrays by protective antibodies [#14, #16, #17]. After invasion, CSP is exported into the hepatocyte cytosol and nucleus, where it outcompetes NF\\u03baB nuclear import to suppress inflammatory gene expression and reprograms host metabolic genes to favor liver-stage growth, and can inhibit host protein synthesis through ribosome association [#9, #12]. CSP-derived peptides are processed and presented on hepatocyte MHC class I to CD8+ T cells, and anti-repeat antibodies neutralize sporozoites in the skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT [#20, #22, #23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing the primary structure of CSP defined its modular architecture and pointed to the conserved flanking regions as candidate liver-cell binding determinants.\",\n      \"evidence\": \"Gene cloning and sequencing with monoclonal antibody peptide inhibition in P. falciparum\",\n      \"pmids\": [\"6204383\", \"6204384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the conserved regions not yet tested experimentally\", \"Repeat region role in motility unknown at this stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Demonstrating that the NANP repeat alone elicits invasion-blocking antibodies identified the repeat as the dominant protective B-cell epitope and vaccine target.\",\n      \"evidence\": \"Recombinant and synthetic-peptide immunization with in vitro sporozoite invasion inhibition of hepatoma cells\",\n      \"pmids\": [\"2988125\", \"2988126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which anti-repeat antibodies block invasion not defined\", \"Role of region I and II antibodies unclear beyond lacking invasion inhibition\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Live imaging showed CSP is deposited as trails and translocated apical-to-posterior by an actin-dependent surface motor, linking CSP directly to gliding motility.\",\n      \"evidence\": \"Immunolocalization and video/electron microscopy of cytochalasin B-immobilized P. berghei sporozoites; motility inhibition by anti-CSP\",\n      \"pmids\": [\"3054075\", \"1787427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular connection between CSP and the motor/adhesin machinery not resolved\", \"Shown in P. berghei only\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Biochemical identification of hepatocyte receptors defined the molecular basis of CSP-mediated host cell targeting.\",\n      \"evidence\": \"Disulfide-dependent region II binding to sulfatides/cholesterol-3-sulfate, HSPG binding via region II-plus, and quantitative LRP binding with invasion assays in P. falciparum/P. berghei\",\n      \"pmids\": [\"1518521\", \"8478608\", \"8920859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of each receptor not fully resolved\", \"Whether receptor engagement precedes or follows N-terminal cleavage unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic dissection assigned distinct in vivo roles to the conserved regions, establishing region II as essential for motility and infectivity.\",\n      \"evidence\": \"Gene replacement of P. berghei CSP with PfCSP region I/II deletion variants and phenotyping of motility, salivary gland invasion, and mouse infection\",\n      \"pmids\": [\"12244064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Region I dispensability in this system leaves its molecular role open\", \"Mechanism by which region II supports motility not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Deletion mapping showed the N-terminus is essential for liver-cell binding independently of the TSR domain, distributing binding function across the protein.\",\n      \"evidence\": \"Systematic truncation of recombinant PfCSP tested in liver-cell binding and invasion inhibition assays\",\n      \"pmids\": [\"11751898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"N-terminal receptor identity not determined\", \"Interplay between N-terminal and region II binding sites unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of a PEXEL/VTS and NLS in CSP revealed a post-invasion effector function in which CSP reprograms the hepatocyte to favor parasite growth.\",\n      \"evidence\": \"Motif identification, hepatocyte expression, NF\\u03baB nuclear import competition, transcriptional profiling, and parasite growth assays in P. falciparum/P. berghei\",\n      \"pmids\": [\"17981117\", \"9669999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners in the host nucleus not identified\", \"Ribosome-association mechanism single-lab and mechanistically incomplete\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Antigen-processing studies defined how CSP epitopes reach MHC class I in hepatocytes and dendritic cells, clarifying the basis of protective CD8+ T-cell responses.\",\n      \"evidence\": \"Transgenic parasites, TAP-deficient and endosomal-mutant mice, proteasome/protease inhibitors, and CTL assays across P. yoelii/P. berghei/P. falciparum\",\n      \"pmids\": [\"21445239\", \"17513754\", \"1689762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the aspartic protease processing CSP not defined\", \"PEXEL-independence of CSP secretion into hepatocytes not mechanistically explained\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Biophysical and crystallographic work resolved the overall shape and domain organization of CSP, defining the extended rod and the composite \\u03b1TSR domain.\",\n      \"evidence\": \"DLS, sedimentation, AFM of recombinant PfCSP and X-ray structure of the region III\\u2013TSR unit\",\n      \"pmids\": [\"19633296\", \"22547819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structure including the repeat region not solved\", \"Ligand for the \\u03b1TSR hydrophobic pocket unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Blocking N-terminal proteolytic cleavage with a monoclonal antibody established that CSP processing is a required step for hepatocyte infection and a distinct protective target.\",\n      \"evidence\": \"mAb5D5 cleavage-inhibition assays and passive transfer in transgenic mice expressing the PfCSP N-terminus\",\n      \"pmids\": [\"25762791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for cleavage not identified\", \"Functional consequence of cleavage for downstream events undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structures of protective antibodies bound to the repeats revealed defined \\u03b2-turn conformations and antibody-organized spiral arrays, explaining the potency of anti-repeat neutralization.\",\n      \"evidence\": \"X-ray of Fab\\u2013(NPNA) complexes, negative-stain EM, and ~3.4-\\u00c5 cryo-EM of rsCSP\\u2013Fab complexes with inter-Fab mutational analysis\",\n      \"pmids\": [\"29138320\", \"30324137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformation of the repeat on the native sporozoite surface not directly observed\", \"In vivo relevance of Fab\\u2013Fab-stabilized arrays not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistic dissection of antibody killing showed anti-repeat mAbs neutralize sporozoites in skin and liver by disrupting motility, blocking invasion, and stripping the coat to expose the membrane to SPECT.\",\n      \"evidence\": \"Intravital microscopy, passive transfer, and complement/FcR\\u03b3-deficient models across P. yoelii/P. berghei/P. falciparum, with bioluminescence-tracked late killing in P. berghei\",\n      \"pmids\": [\"30349082\", \"39951341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Late intracellular killing mechanism studied with a single antibody in P. berghei\", \"How coat stripping mechanistically engages SPECT not fully defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Single-molecule force measurements established that the CSP repeat acts as an elastic spring whose length-dependent stiffness is required for TRAP-containing adhesion site assembly and gliding motility.\",\n      \"evidence\": \"Repeat truncation/scramble mutants, gliding assays, adhesion-site imaging, and single-molecule fluorescence-force spectroscopy in P. berghei/P. falciparum\",\n      \"pmids\": [\"40983687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical link between the CSP spring and TRAP not resolved\", \"Whether repeat elasticity influences receptor binding untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identities of the N-terminal receptor and the protease that cleaves the CSP N-terminus, and the direct host nuclear/ribosomal partners of exported CSP, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"N-terminal hepatocyte receptor unidentified\", \"Cleavage protease unidentified\", \"Direct host-factor targets of nuclear CSP not defined\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [6, 8, 18]},\n      {\"term_id\": \"GO:0046625\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005044\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0043022\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0042277\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0046658\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [9, 12, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071693\", \"supporting_discovery_ids\": [4, 5, 11, 21]},\n      {\"term_id\": \"GO:0044409\", \"supporting_discovery_ids\": [6, 7, 8, 10]},\n      {\"term_id\": \"GO:0002479\", \"supporting_discovery_ids\": [19, 22, 23]},\n      {\"term_id\": \"GO:0043124\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"CSP\\u2013TRAP-containing adhesion site (functional association) [#21]\",\n      \"recombinant shortened CSP\\u2013Fab helical/spiral complexes [#16, #17]\"\n    ],\n    \"partners\": [\n      \"Heparan sulfate proteoglycans (syndecan-like) [#6, #18]\",\n      \"LDL receptor-related protein (LRP) [#8]\",\n      \"Sulfatides / cholesterol-3-sulfate [#7]\",\n      \"Host ribosomes / rough microsomes [#9]\",\n      \"NF\\u03baB (nuclear import competition) [#12]\",\n      \"TRAP (adhesion site) [#21]\",\n      \"SPECT (exposed upon coat stripping) [#20]\"\n    ],\n    \"other_free_text\": [\n      \"412-aa protein with N-terminal conserved region, central NANP/NVDP tandem repeats, and conserved region II shared across Plasmodium species [#0, #1]\",\n      \"Region III and TSR fold into a single \\u03b1TSR domain with a hydrophobic pocket that does not bind heparin [#14]\",\n      \"Extended rod-like structure ~21\\u201325 nm long; repeat region behaves as a length-dependent elastic spring [#13, #21]\",\n      \"N-terminal proteolytic cleavage is required for hepatocyte infection [#15]\",\n      \"Exported to hepatocyte cytosol/nucleus via PEXEL/VTS and NLS to reprogram host transcription and metabolism [#12]\",\n      \"CSP epitopes processed via proteasome-, TAP-, and aspartic-protease-dependent pathways for MHC class I presentation [#19, #23]\",\n      \"Species divergence: motility/CSP trail and antibody-killing work largely in P. berghei/P. yoelii; receptor binding and structural work largely in P. falciparum [#4, #5, #20, #24, #6, #14]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0304600","name":null,"product":"circumsporozoite (CS) protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0403200","name":null,"product":"circumsporozoite (CS) protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0838500","name":null,"product":"circumsporozoite (CS) protein","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CSP","evaluation":null}