Affinage · Plasmodium

PF3D7_1200610

VAR2CSA uORF

Audit flag: identity unverified
Annotated
2026-09-08
93 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VAR2CSA (PF3D7_1200610) is a ~350 kDa PfEMP1 variant surface antigen displayed on knobs of P. falciparum-infected erythrocytes that mediates placental sequestration by binding chondroitin sulfate A (CSA) (PMID:15520249, PMID:17095277, PMID:31098405). Its full-length extracellular region binds CSA with nanomolar affinity and strict glycosaminoglycan specificity that individual DBL domains cannot reproduce, indicating that high-affinity CSA recognition emerges from cooperative interdomain organization (PMID:20194779, PMID:20109466); cryo-EM of the full-length ectodomain shows a stable core flanked by a flexible arm, with CSA threading two channels in the core without inducing major conformational change, and the core CSA-binding determinants centered on DBL2X and flanking interdomain regions being conserved while surrounded by polymorphic segments (PMID:33452495, PMID:22570492). Native binding depends on 4-O-sulfated disaccharides and glucuronic acid with a minimum chain length of eight monosaccharides, and cytoadhesion is cooperative, shear-induced and sensitive to CSA receptor spacing, allowing discrimination of the placental CSA milieu presented by syndecan-1 on the syncytiotrophoblast (PMID:17562715, PMID:25352129, PMID:27556547). VAR2CSA also binds nonimmune IgM via DBL3X and DBL5ε, masking protective IgG epitopes and blocking FcγR-dependent phagocytosis without compromising CSA adhesion (PMID:21746929, PMID:16945914). Expression is controlled by a 5'-UTR upstream open reading frame (uORF) that represses translation of the downstream VAR2CSA-encoding ORF via ribosome reinitiation, a block relieved by the translation-enhancing factor PTEF after PfCalpain processing (PMID:19119419, PMID:23980802, PMID:28481333); the same uORF destabilizes var2csa mRNA through nonsense-mediated decay, and together with transient locus activation, noncoding RNAs, and loss of repressive H3K9me3 with repositioning away from telomeric heterochromatin, this positions var2csa as a coordinated switching hub for the var gene family (PMID:36515978, PMID:41851501, PMID:41984626). Surface adhesion is further tuned post-translationally: CK2α phosphorylation at S1068 is required for VAR2CSA trafficking to the erythrocyte surface, and FIKK1 phosphorylation within DBL1-3 enhances CSA binding (PMID:39804934, PMID:42525717). Beyond placental biology, recombinant VAR2CSA recognizes oncofetal CSA on malignant cells, enabling tumor-targeting applications (PMID:26461094).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 Medium

    Establishing that VAR2CSA itself is the antigen on the surface of placental-sequestering parasites answered which PfEMP1 variant underlies pregnancy-associated malaria.

    Evidence Flow cytometry/ELISA with recombinant VAR2CSA domains on CSA-selected infected erythrocytes plus parity-dependent serology

    PMID:15520249

    Open questions at the time
    • Serological rather than genetic demonstration
    • Does not define the CSA-binding domains or affinity
  2. 2006 Medium

    Mapping cytoadhesion-inhibitory epitopes to DBL5ε/DBL6ε (with cross-reactivity to DBL2x/DBL3x) and immunoprecipitating a native ~350 kDa ligand tied specific VAR2CSA domains to adhesion and vaccine-relevant immunity.

    Evidence Mouse monoclonal antibodies, native immunoprecipitation, CHO surface display of individual domains, CSA adhesion inhibition

    PMID:17095277

    Open questions at the time
    • Domain-level, not residue-level epitope resolution
    • Does not resolve which domain forms the core CSA site
  3. 2007 High

    Defining the CSA structural requirements for native VAR2CSA binding explained the biochemical basis of receptor specificity and isolate variation.

    Evidence Direct binding of native PfEMP1 to defined CS oligosaccharide neoglycolipid probes; adhesion inhibition across isolates

    PMID:17562715

    Open questions at the time
    • Does not localize the binding site on the protein
    • Isolate motif preferences correlated but not mechanistically explained
  4. 2010 High

    Recombinant full-length ectodomain studies established that specific high-affinity CSA binding requires cooperative interdomain assembly rather than any single DBL domain.

    Evidence HEK293- and insect-cell-expressed full-length VAR2CSA; SPR affinity (KD ~61 nM); SAXS/AUC; antibody adhesion inhibition

    PMID:20109466 PMID:20194779

    Open questions at the time
    • Compact architecture inferred from low-resolution SAXS
    • Exact CSA contact residues unresolved
  5. 2012 High

    Truncation and modeling localized the core CSA-binding site to DBL2X and flanking interdomain regions, and showed binding is not solely dependent on sulfation, refining the receptor-recognition model.

    Evidence SPR of truncation constructs; SAXS modeling; sulfate-binding-site mutagenesis

    PMID:22570492

    Open questions at the time
    • A DBL1X-3X fragment was reported minimal elsewhere, leaving the precise minimal region unsettled
    • Non-sulfate contributions not molecularly defined
  6. 2016 High

    Identifying syndecan-1 as the syncytiotrophoblast receptor and its CS chains as the ligand established the host cellular target of placental sequestration.

    Evidence VAR2CSA pull-down from placental extracts; immunofluorescence; proximity ligation; Src signaling in syncytialized BeWo cells

    PMID:27556547

    Open questions at the time
    • Physiological consequence of impaired Src signaling for infection not established
    • Other CSPGs detected but roles undefined
  7. 2021 High

    Cryo-EM of the full-length ectodomain resolved the compact core/flexible-arm architecture and how CSA traverses two channels, providing the structural basis of conserved CSA binding amid polymorphic surfaces.

    Evidence Cryo-EM of full-length ectodomain from NF54 with CSA and from FCR3 alone

    PMID:33452495

    Open questions at the time
    • Does not resolve how phosphorylation modulates the binding channels
    • Membrane-proximal and transmembrane regions not addressed
  8. 2011 High

    Demonstrating that nonimmune IgM binds DBL3X/DBL5ε to block IgG and phagocytosis without affecting CSA adhesion revealed a dedicated immune-evasion function distinct from adhesion.

    Evidence Monoclonal IgG binding, IgM competition, FcγR phagocytosis, C1q deposition, and CSA adhesion assays

    PMID:16945914 PMID:21746929

    Open questions at the time
    • Structural basis of IgM/IgG epitope overlap not defined
    • In vivo contribution to placental infection not quantified
  9. 2019 High

    Quantifying endogenous VAR2CSA at 3–4 molecules per knob tip via super-resolution imaging defined the physical presentation of the adhesin, relevant to the cooperative, spacing-dependent adhesion observed biophysically.

    Evidence PALM microscopy of mEOS2-tagged endogenous VAR2CSA; quantitative FACS; immuno-EM

    PMID:25352129 PMID:31098405

    Open questions at the time
    • Link between per-knob density and in vivo avidity not directly tested
    • How spacing discrimination selects placenta over other tissues not molecularly resolved
  10. 2013 High

    Dissecting the uORF/reinitiation switch explained how abundant var2csa transcript is decoupled from protein output, resolving the post-transcriptional layer of VAR2CSA control.

    Evidence Reporter constructs in stably transformed P. falciparum measuring reinitiation efficiency, building on the 2009 uORF discovery and the 2008 high-transcription/low-protein observation

    PMID:18431472 PMID:19119419 PMID:23980802

    Open questions at the time
    • Trans-acting factors not identified in these studies
    • Signal triggering derepression during CSA selection undefined here
  11. 2017 High

    Identifying PTEF as the factor that relieves uORF repression after PfCalpain processing supplied the trans-acting machinery driving VAR2CSA translation.

    Evidence Genetic manipulation of PTEF, ribosome co-IP, PfCalpain proteolysis, heterologous translation; separately CRISPR deletion of the var2csa intron

    PMID:28481333 PMID:28698275

    Open questions at the time
    • Upstream signal controlling PTEF/PfCalpain activity unknown
    • Intron contribution to switching only subtle
  12. 2022 High

    Showing that the uORF drives NMD-mediated mRNA destabilization and that noncoding RNAs and transient activation govern switching established var2csa as a coordinating switching hub for the var family.

    Evidence Genetic manipulation of the var2csa locus; switching assays; noncoding RNA characterization; NMD pathway analysis

    PMID:36515978 PMID:41851501

    Open questions at the time
    • Molecular link between NMD and activation of alternative var genes not fully defined
    • Identity of the noncoding RNA effectors incomplete
  13. 2026 High

    Coupling var2csa activation to H3K9me3 depletion and repositioning away from telomeric heterochromatin, and mapping CK2α(S1068) and FIKK1(S429/T934) phosphorylation, added the epigenetic and post-translational regulatory layers governing expression and adhesion.

    Evidence ChIP-seq/Hi-C/bisulfite sequencing; in vitro kinase assays with CK2α and FIKK1; CRISPR S1068A knock-in; conditional FIKK1 knockout; CSA adhesion assays

    PMID:39804934 PMID:41984626 PMID:42525717

    Open questions at the time
    • How CK2α traffics to and modifies the ectodomain in vivo not fully resolved
    • Interplay between phosphorylation and the structural CSA channels untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers (epigenetic activation, uORF/NMD, PTEF-mediated derepression, CK2α/FIKK1 phosphorylation) are integrated and temporally sequenced to convert transcriptional activation into surface-displayed, adhesion-competent VAR2CSA remains unresolved.
  • No unified model linking derepression signals to phosphorylation-dependent trafficking
  • Upstream cues that initiate the switch in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
CHONDROITIN SULFATE A (CSA)CK2Α (HOST AND PARASITE)FIKK1NONIMMUNE IGMONCOFETAL CHONDROITIN SULFATE / CD44 / CSPG4PFCALPAINPTEF (TRANSLATION ENHANCING FACTOR)RIBOSOMESYNDECAN-1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 The var2csa mRNA contains a small upstream open reading frame (uORF) in its 5'-UTR that represses translation of the downstream VAR2CSA-encoding ORF. Using cultured parasite lines and reporter gene constructs, this translational repression was shown to be reversible, allowing high levels of VAR2CSA protein translation upon selection for CSA-binding. Reporter gene constructs in stably transformed P. falciparum parasites; in vitro parasite culture with selection PLoS pathogens High 19119419
2013 The molecular switch controlling VAR2CSA translation involves two components: (i) active translation of the uORF and (ii) sequence-specific characteristics of the surrounding transcript, which together control the ability of the ribosome to reinitiate translation at the downstream VAR2CSA-encoding ORF. Proper regulation of switching relies on ribosome reinitiation efficiency. Stable transformation of P. falciparum with reporter gene constructs; analysis of reinitiation efficiency by measuring downstream ORF translation Molecular microbiology High 23980802
2017 The P. falciparum translation enhancing factor (PTEF) relieves uORF-mediated repression of VAR2CSA translation. PTEF requires proteolytic processing by PfCalpain to generate a C-terminal domain containing a sterile-alpha-motif-like domain. This C-terminal domain shuttles to the cytoplasm, interacts with ribosomes, and facilitates translational derepression of the var2csa coding sequence. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on PTEF expression level. Genetic manipulation of PTEF levels in P. falciparum; co-immunoprecipitation with ribosomes; proteolysis assays with PfCalpain; heterologous translation system Nature microbiology High 28481333
2008 VAR2CSA switches to a default state of high transcription but sparse translation into PfEMP1 protein when parasites spontaneously switch var gene expression. Despite abundant var2csa transcripts, intracellular VAR2CSA PfEMP1 levels were low, indicating post-transcriptional repression contributes to regulation of VAR2CSA protein expression. Long-term propagation of clonal P. falciparum lines without enrichment; var gene transcription monitoring; PfEMP1 surface expression assays; nuclear repositioning analysis PloS one Medium 18431472
2017 CRISPR/Cas9-mediated deletion of the var2csa intron (PfEMP1-encoding gene Pf3D7_1200600) in its endogenous chromosomal context resulted in upregulation of var2csa transcription in ring-stage parasites and subsequent VAR2CSA PfEMP1 expression in late-stage parasites. The intron is not required for transcriptional silencing or activation but contributes subtly to regulation of var switching frequency. CRISPR/Cas9 genome editing of endogenous var2csa intron in P. falciparum 3D7; transcriptional analysis; CSA panning; CD36 receptor panning mBio High 28698275
2025 Human and P. falciparum Casein Kinase 2α (CK2α) phosphorylate the extracellular region of VAR2CSA. Mass spectrometry and site-directed mutagenesis identified residue S1068 in VAR2CSA as phosphorylated by both CK2α enzymes and associated with CSA binding. CRISPR/Cas9-mediated S1068A mutation strongly impairs infected erythrocyte adhesion by abolishing VAR2CSA translocation to the erythrocyte surface. CK2 inhibitors reduce infected erythrocyte adhesion to CSA. In vitro kinase assays with recombinant CK2α; mass spectrometry; site-directed mutagenesis; CRISPR/Cas9 generation of phosphoresidue mutant parasites; immunofluorescence; CSA adhesion assays PLoS pathogens High 39804934
2026 FIKK1, a P. falciparum FIKK kinase family member exported to Maurer's Clefts, phosphorylates VAR2CSA in vitro on residues including S429 and T934 in the DBL1-3 domains, and this phosphorylation increases recombinant VAR2CSA binding to CSA. Rapamycin-induced knockout of FIKK1 in transgenic P. falciparum reduces infected erythrocyte cytoadhesion to CSA without affecting VAR2CSA expression levels. FIKK1 co-localizes with VAR2CSA at Maurer's Cleft puncta by immunofluorescence. In vitro kinase assay; inducible DiCre-based FIKK1 knockout; immunofluorescence assay; CSA cytoadhesion assay; mass spectrometry of phosphorylation sites PLoS pathogens High 42525717
2021 Cryo-EM structures of full-length VAR2CSA ectodomain from P. falciparum strain NF54 in complex with CSA, and from strain FCR3 alone, revealed that VAR2CSA has a stable core domain flanked by a flexible arm. CSA traverses the core domain by binding within two channels, and CSA binding does not induce major conformational changes in VAR2CSA. CSA-binding elements are conserved across VAR2CSA variants and are flanked by polymorphic segments. Cryo-electron microscopy structure determination of full-length VAR2CSA ectodomain with and without CSA Nature microbiology High 33452495
2010 Full-length recombinant VAR2CSA extracellular region (DBL1X to DBL6ε) expressed in HEK293 cells binds CSA with high affinity (KD = 61 nM) and specificity, whereas individual DBL domains lack this high-affinity specific binding. Structural characterization by analytical ultracentrifugation and SAXS revealed a compact organization governed by specific interdomain interactions rather than an extended structure, indicating a higher-order CSA-binding site formed by domain cooperation. Recombinant protein expression in HEK293 cells; surface plasmon resonance binding assays; analytical ultracentrifugation; small-angle X-ray scattering (SAXS) Proceedings of the National Academy of Sciences of the United States of America High 20194779
2010 Full-length recombinant VAR2CSA expressed from insect cells binds human chondroitin sulfate proteoglycan with nanomolar affinity via surface plasmon resonance, with significantly weaker binding to other glycosaminoglycans, matching the specificity of infected erythrocytes. Antibodies against full-length VAR2CSA completely inhibit both recombinant VAR2CSA and parasite binding to chondroitin sulfate proteoglycan. Recombinant protein expression in insect cells; surface plasmon resonance; parasite adhesion inhibition assay Journal of molecular biology High 20109466
2012 The core CSA-binding site of VAR2CSA lies within the DBL2X domain and flanking interdomain regions. Truncation analysis by biosensor technology showed this minimal region is sufficient for specific CSA binding. SAXS modeling placed the CSA-binding DBL2X domain in the center of the VAR2CSA structure. Mutagenesis of classic sulfate-binding sites and ionic interaction tests showed CSA binding is not solely dependent on the sulfated CSA structure. Truncation constructs of VAR2CSA tested by biosensor (surface plasmon resonance); SAXS-based structural modeling; sulfate-binding site mutagenesis The Journal of biological chemistry High 22570492
2011 The minimal VAR2CSA region retaining high-affinity and specificity for CSA binding equivalent to the full-length extracellular region is the DBL1X-3X fragment. Additionally, inhibitory antibodies raised against full-length DBL1X-6ε primarily target DBL3X and, to a lesser extent, DBL5ε. Recombinant truncated VAR2CSA protein expression; glycosaminoglycan binding assays; rabbit immunization with antibody inhibition mapping PloS one Medium 21625526
2004 VAR2CSA protein is expressed on the surface of CSA-selected infected erythrocytes, as demonstrated by recognition with antibodies that are acquired in a sex-specific and parity-dependent manner in endemic populations, confirming surface expression of VAR2CSA as the key antigen of placental parasites. Flow cytometry and ELISA using recombinant VAR2CSA domains; surface expression assay on CSA-selected infected erythrocytes; epidemiological serological analysis The Journal of experimental medicine Medium 15520249
2016 VAR2CSA-mediated placental sequestration occurs specifically through binding of chondroitin sulfate (CS) attached to syndecan-1 on the syncytiotrophoblast. VAR2CSA pull-down experiments from placental extracts identified three CSPGs; immunofluorescence and proximity ligation assays showed syndecan-1 is the main receptor for VAR2CSA-mediated placental adherence. rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in syncytialized BeWo cells. VAR2CSA pull-down from placental extracts; immunofluorescence; proximity ligation assay; Src signaling assay in BeWo cells with forskolin-induced syncytial fusion PLoS pathogens High 27556547
2007 Native PfEMP1 encoded by var2csa binds directly to immobilized CSA in a manner dependent on 4-O-sulfated disaccharides and glucuronic acid. The minimum chain length for direct PfEMP1 binding is eight monosaccharide units. Parasite isolates expressing different var2csa variants show isolate-specific differences in preferred CSA structural motifs that correlate with polymorphisms in the encoded PfEMP1. Direct binding assay with native PfEMP1 isolated from infected erythrocytes; immobilized CS oligosaccharides as neoglycolipid probes; adhesion inhibition assays with defined P. falciparum isolates The Journal of biological chemistry High 17562715
2006 A VAR2CSA variant that binds CSA also harbors IgG- and IgM-binding domains, specifically in DBL2-X, DBL5-epsilon, and DBL6-epsilon. CSA-binding and nonimmune IgG/IgM binding are linked phenotypes of in vitro-adapted parasites. Multiple receptor binding (IgG/IgM/HA/CSA) rather than exclusive CSA binding characterizes fresh placental isolates. In vitro parasite selection; antibody binding characterization to individual VAR2CSA DBL domains expressed on cell surfaces; analysis of ex vivo placental isolates Proceedings of the National Academy of Sciences of the United States of America Medium 16945914
2011 Nonspecific IgM binds to the DBL3X and DBL5ε domains of VAR2CSA-expressing infected erythrocytes and blocks subsequent specific IgG binding to these domains, thereby protecting parasites from FcγR-dependent phagocytosis. This IgM masking did not affect IE adhesion to CSA or lead to C1q deposition, indicating it evolved specifically to evade acquired immunity without compromising VAR2CSA adhesion function. Human monoclonal IgG binding assays; IgM competition assays on VAR2CSA-expressing infected erythrocytes; FcγR-dependent phagocytosis assay; C1q deposition assay; CSA adhesion assay Proceedings of the National Academy of Sciences of the United States of America High 21746929
2014 Cytoadhesion of VAR2CSA-expressing infected erythrocytes to chondroitin-4-sulfate is strongly dependent on CSA receptor spacing (half-maximal adhesion at CSA distance 9 ± 1 nm), is cooperative, and is shear stress-induced. These findings suggest allosteric effects within VAR2CSA contribute to discriminating between different CSA milieus (e.g., placenta versus other tissues). Artificial membranes with defined CSA spacing intervals; flow chamber cytoadhesion assays at varied hydrodynamic conditions Blood Medium 25352129
2019 VAR2CSA is present on knobs of infected erythrocytes at a density of 3.3 ± 1.7 molecules per knob (wild-type hemoglobin) and 4.3 ± 2.5 per knob (sickle hemoglobin), predominantly placed on the knob tip. This was determined using super-resolution microscopy of parasites expressing a mEOS2-tagged VAR2CSA from the endogenous var2csa locus, verified by quantitative FACS and immuno-electron microscopy. Super-resolution (PALM) microscopy with photoactivatable mEOS2 fused to endogenous VAR2CSA; quantitative FACS; immuno-electron microscopy with stereology Communications biology High 31098405
2009 In P. falciparum line HB3, where var2csa is duplicated, the two var2csa copies are simultaneously transcribed both at the population level and in individual cells, with nuclear co-localization of active genes and transcripts. This challenges the dogma of mutually exclusive var gene transcription and indicates both duplicated var2csa copies can be transcriptionally functional. Real-time PCR allelic discrimination; discriminative RNA-FISH; nuclear co-localization imaging Genome biology Medium 19849836
2022 var2csa functions as a universally conserved 'switching hub' that coordinates var gene transcriptional switching. A structured switching bias shifts over time, shaping var expression patterns. Transient activation of the var2csa locus mediates var switching, while non-coding RNAs from this locus contribute to repression of var2csa transcription and affect var switching frequencies. The uORF in the var2csa 5'-UTR destabilizes var2csa mRNA through nonsense-mediated RNA decay (NMD), promoting transcriptional activation of alternative var genes. Genetic manipulation of P. falciparum var2csa locus; var gene switching analysis; noncoding RNA characterization; NMD pathway analysis eLife High 36515978
2026 Transient activation of the var2csa locus mediates var switching; non-coding RNAs from the var2csa locus contribute to repression of var2csa transcription and affect var switching frequencies; and the uORF in the var2csa 5'-UTR destabilizes var2csa mRNA through nonsense-mediated RNA decay (NMD), promoting transcriptional activation of alternative var genes, thus enabling var2csa to function as a switching hub. Genetic manipulation of P. falciparum var2csa locus; noncoding RNA analysis; NMD pathway interrogation; var gene switching assays The EMBO journal High 41851501
2026 Transcriptional activation of var2csa is strongly associated with depletion of repressive H3K9me3 histone marks and with a small but significant repositioning of the var2csa locus away from heterochromatic telomeric clusters, as determined by chromatin conformation capture. 5-methylcytosine occupancy was present in all var genes but was independent of transcriptional repression and switching. ChIP-seq for H3K9me3; chromatin conformation capture (Hi-C); bisulfite sequencing for 5-methylcytosine; phenotypically homogeneous VAR2CSA-expressing parasite populations eLife High 41984626
2015 Recombinant VAR2CSA (rVAR2) binds a distinct type of chondroitin sulfate (oncofetal CS) that is present on malignant cells and a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4, but is absent from most normal tissues. rVAR2 localizes to tumors in vivo, and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin inhibits in vivo tumor cell growth and metastasis. Binding assays with recombinant VAR2CSA on tumor cell lines and tissues; in vivo tumor localization imaging; rVAR2-toxin/drug conjugate tumor growth inhibition in mouse models Cancer cell High 26461094
2006 Mouse monoclonal antibodies raised against CSA-binding P. falciparum identified DBL5ε and DBL6ε as the targets of cytoadhesion-inhibiting antibodies, with some antibodies also cross-reacting with DBL2x or DBL3x, suggesting shared epitopes across VAR2CSA domains. Native var2CSA was immunoprecipitated as a 350 kDa PfEMP1, and this purified native ligand elicited adhesion-inhibitory antibodies in mice. Mouse monoclonal antibody generation; immunoprecipitation of native VAR2CSA; CHO cell surface expression of individual VAR2CSA domains; CSA adhesion inhibition assay Microbes and infection Medium 17095277

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. The Journal of experimental medicine 488 15520249
2007 Malaria in pregnancy: pathogenesis and immunity. The Lancet. Infectious diseases 406 17251081
2018 Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. The Lancet. Infectious diseases 227 29396010
2015 Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer cell 175 26461094
2012 Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. The Journal of biological chemistry 149 22570492
2010 Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. Proceedings of the National Academy of Sciences of the United States of America 128 20194779
2018 The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner. Nature communications 126 30115931
2018 Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice. Theranostics 107 29774074
2020 PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study. The Lancet. Infectious diseases 106 32032566
2007 Structural polymorphism and diversifying selection on the pregnancy malaria vaccine candidate VAR2CSA. Molecular and biochemical parasitology 103 17669514
2010 Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies. Journal of molecular biology 97 20109466
2012 New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. The Journal of infectious diseases 84 22966126
2016 Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1. PLoS pathogens 80 27556547
2015 Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin. Emerging infectious diseases 80 25898123
2011 Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1. Proceedings of the National Academy of Sciences of the United States of America 72 21746929
2006 Dynamics of anti-VAR2CSA immunoglobulin G response in a cohort of senegalese pregnant women. The Journal of infectious diseases 72 16453268
2009 An upstream open reading frame controls translation of var2csa, a gene implicated in placental malaria. PLoS pathogens 71 19119419
2011 Var2CSA minimal CSA binding region is located within the N-terminal region. PloS one 64 21625526
2020 Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review. BMC medicine 63 31941488
2021 Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA. Nature microbiology 61 33452495
2021 Poor Birth Outcomes in Malaria in Pregnancy: Recent Insights Into Mechanisms and Prevention Approaches. Frontiers in immunology 60 33790894
2015 Designing a VAR2CSA-based vaccine to prevent placental malaria. Vaccine 58 26469717
2013 Malaria, primigravidae, and antibodies: knowledge gained and future perspectives. Trends in parasitology 56 24388420
2012 High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria. PloS one 56 22761948
2008 VAR2CSA expression on the surface of placenta-derived Plasmodium falciparum-infected erythrocytes. The Journal of infectious diseases 56 18700835
2019 Capture and Detection of Circulating Glioma Cells Using the Recombinant VAR2CSA Malaria Protein. Cells 55 31466397
2006 Antigenic differences and conservation among placental Plasmodium falciparum-infected erythrocytes and acquisition of variant-specific and cross-reactive antibodies. The Journal of infectious diseases 55 16453269
2021 Afucosylated Plasmodium falciparum-specific IgG is induced by infection but not by subunit vaccination. Nature communications 54 34611164
2012 High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infection and immunity 54 22331427
2006 Nonimmune immunoglobulin binding and multiple adhesion characterize Plasmodium falciparum-infected erythrocytes of placental origin. Proceedings of the National Academy of Sciences of the United States of America 54 16945914
2010 The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development. Human vaccines 53 19823032
2010 Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants. Journal of immunology (Baltimore, Md. : 1950) 53 21078904
2008 Default Pathway of var2csa switching and translational repression in Plasmodium falciparum. PloS one 53 18431472
2007 Six genes are preferentially transcribed by the circulating and sequestered forms of Plasmodium falciparum parasites that infect pregnant women. Infection and immunity 53 17698567
2007 Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens. The Journal of infectious diseases 52 17538896
2015 A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA. PloS one 51 26599509
2015 Investigating the function of Fc-specific binding of IgM to Plasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting. Cellular microbiology 49 25482886
2015 Identification of malaria parasite-infected red blood cell surface aptamers by inertial microfluidic SELEX (I-SELEX). Scientific reports 48 26126714
2006 Characterization of anti-var2CSA-PfEMP1 cytoadhesion inhibitory mouse monoclonal antibodies. Microbes and infection 46 17095277
2012 The density of knobs on Plasmodium falciparum-infected erythrocytes depends on developmental age and varies among isolates. PloS one 45 23029166
2007 VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria. Parasitology 45 17958922
2007 Antibodies among men and children to placental-binding Plasmodium falciparum-infected erythrocytes that express var2csa. The American journal of tropical medicine and hygiene 44 17620626
2018 Global genetic diversity of var2csa in Plasmodium falciparum with implications for malaria in pregnancy and vaccine development. Scientific reports 43 30337594
2013 A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria. Molecular microbiology 40 23980802
2015 The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine. PloS one 39 26327283
2012 A plasma survey using 38 PfEMP1 domains reveals frequent recognition of the Plasmodium falciparum antigen VAR2CSA among young Tanzanian children. PloS one 39 22295123
2021 Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria. eLife 37 34181872
2011 Parity and placental infection affect antibody responses against Plasmodium falciparum during pregnancy. Infection and immunity 37 21300778
2021 Progress and Insights Toward an Effective Placental Malaria Vaccine. Frontiers in immunology 34 33717176
2019 Single-molecule imaging and quantification of the immune-variant adhesin VAR2CSA on knobs of Plasmodium falciparum-infected erythrocytes. Communications biology 34 31098405
2010 Of mice and women: rodent models of placental malaria. Trends in parasitology 33 20605743
2016 VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies to Plasmodium falciparum Placental Malaria. The Journal of infectious diseases 31 27190180
2014 Functional antibodies against VAR2CSA in nonpregnant populations from colombia exposed to Plasmodium falciparum and Plasmodium vivax. Infection and immunity 31 24686068
2014 Cytoadhesion of Plasmodium falciparum-infected erythrocytes to chondroitin-4-sulfate is cooperative and shear enhanced. Blood 31 25352129
2019 Evasion of Classical Complement Pathway Activation on Plasmodium falciparum-Infected Erythrocytes Opsonized by PfEMP1-Specific IgG. Frontiers in immunology 30 30666256
2009 Simultaneous transcription of duplicated var2csa gene copies in individual Plasmodium falciparum parasites. Genome biology 30 19849836
2017 Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor. Nature microbiology 29 28481333
2007 Structural basis for binding of Plasmodium falciparum erythrocyte membrane protein 1 to chondroitin sulfate and placental tissue and the influence of protein polymorphisms on binding specificity. The Journal of biological chemistry 29 17562715
2017 Increased risk of low birth weight in women with placental malaria associated with P. falciparum VAR2CSA clade. Scientific reports 28 28801627
2017 Plasmodium falciparum PfEMP1 Modulates Monocyte/Macrophage Transcription Factor Activation and Cytokine and Chemokine Responses. Infection and immunity 28 29038124
2008 Identification of glycosaminoglycan binding regions in the Plasmodium falciparum encoded placental sequestration ligand, VAR2CSA. Malaria journal 28 18534039
2008 Preferential transcription of conserved rif genes in two phenotypically distinct Plasmodium falciparum parasite lines. International journal for parasitology 28 19162031
2019 Placental malaria vaccine candidate antigen VAR2CSA displays atypical domain architecture in some Plasmodium falciparum strains. Communications biology 27 31840102
2008 VAR2CSA domains expressed in Escherichia coli induce cross-reactive antibodies to native protein. The Journal of infectious diseases 27 18462161
2022 A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites. eLife 25 36515978
2019 Preclinical immunogenicity and safety of the cGMP-grade placental malaria vaccine PRIMVAC. EBioMedicine 25 30885725
2018 Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes. Malaria journal 25 29523137
2017 CRISPR/Cas9 Genome Editing Reveals That the Intron Is Not Essential for var2csa Gene Activation or Silencing in Plasmodium falciparum. mBio 25 28698275
2008 Differential evolution of anti-VAR2CSA- IgG3 in primigravidae and multigravidae pregnant women infected by Plasmodium falciparum. Malaria journal 24 18190692
2022 A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates. eLife 23 35103596
2018 IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax. Infection and immunity 23 29784859
2018 Down-selection of the VAR2CSA DBL1-2 expressed in E. coli as a lead antigen for placental malaria vaccine development. NPJ vaccines 23 30038803
2010 The kinetics of antibody binding to Plasmodium falciparum VAR2CSA PfEMP1 antigen and modelling of PfEMP1 antigen packing on the membrane knobs. Malaria journal 21 20403153
2021 Allelic variants of full-length VAR2CSA, the placental malaria vaccine candidate, differ in antigenicity and receptor binding affinity. Communications biology 20 34799664
2019 Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA. mBio 20 31594821
2021 VAR2CSA-Mediated Host Defense Evasion of Plasmodium falciparum Infected Erythrocytes in Placental Malaria. Frontiers in immunology 19 33633743
2019 Cross-Species Immune Recognition Between Plasmodium vivax Duffy Binding Protein Antibodies and the Plasmodium falciparum Surface Antigen VAR2CSA. The Journal of infectious diseases 19 30534974
2025 Casein Kinases 2-dependent phosphorylation of the placental ligand VAR2CSA regulates Plasmodium falciparum-infected erythrocytes cytoadhesion. PLoS pathogens 7 39804934
2025 Fc-Afucosylation of VAR2CSA-Specific Immunoglobulin G and Clinical Immunity to Placental Plasmodium falciparum Malaria. The Journal of infectious diseases 5 39585195
2025 Exploring the P. falciparum antigens associated with reduced risk of malaria in pregnancy. Frontiers in immunology 2 40726979
2025 VAR2CSA-reactive IgG in Brazilian women exposed to Plasmodium falciparum or P. vivax infection during pregnancy. Infection and immunity 2 41170961
2025 Identification of Plasmodium falciparum VAR2CSA peptides differentially recognized by IgG of multigravidae through epitope excision. Frontiers in immunology 2 41293178
2026 Epigenetics and chromatin structure regulate var2csa expression and the placental-binding phenotype in Plasmodium falciparum. eLife 1 41984626
2025 The molecular basis of coordinated antigen switching enabling chronic infection by human malaria parasites. bioRxiv : the preprint server for biology 1 40791317
2026 Epigenetics and chromatin structure regulate var2csa expression and the placental binding phenotype in Plasmodium falciparum. bioRxiv : the preprint server for biology 0 41648338
2026 Two divergent VAR2CSA lineages with distinct evolutionary signatures circulate in Plasmodium falciparum from Thailand. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 0 41791500
2026 Mechanistic insights into coordinated var transcriptional switching in malaria parasites. The EMBO journal 0 41851501
2026 Beyond VAR2CSA: redefining the antigenic landscape of placental malaria vaccines. Open research Africa 0 42405012
2026 Afucosylated VAR2CSA-Specific IgG Reduces Risks of Placental Malaria. The Journal of infectious diseases 0 42446379
2026 FIKK1, a member of the FIKK kinase family, phosphorylates VAR2CSA and regulates adhesion of Plasmodium falciparum-infected erythrocytes to the placental receptor CSA. PLoS pathogens 0 42525717
2026 Malaria and cancer: common features and interactions. Trends in parasitology 0 42527283
2025 Expression of Concern for Lopez-Perez et al., "IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax". Infection and immunity 0 39804056
2025 Machine learning framework to extract physicochemical features of B-cell epitopes recognized by a cross-reactive antibody. NPJ systems biology and applications 0 41038839