VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies to<i>Plasmodium falciparum</i>Placental Malaria

Doritchamou, Justin; Herrera, Raúl; Aebig, Joan; Morrison, Robert; Nguyen, Vu; Reiter, Karine; Shimp, Richard L.; MacDonald, Nicholas J.; Narum, David L.; Fried, Michal; Duffy, Patrick E.

doi:10.1093/infdis/jiw197

Cited by 36 publications

(38 citation statements)

References 48 publications

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“…In this study, high levels of antibody reactivity to recombinant DBL3 FCR3 were associated with greater BIA against NF54 but not against the FCR3 isolate. This observation is consistent with our previous report showing that anti-DBL3 antibodies purified from multigravidae had no BIA against the homologous isolate yet disrupted binding of a heterologous parasite to CSA (16). This unexpected failure of BIA against the homologous FCR3 parasite may be explained by allele-specific nonfunctional anti-DBL3 FCR3 antibodies that impede the binding of functional antibodies (51), but this hypothesis requires additional study.…”

Section: Discussionsupporting

confidence: 92%

“…Here, the parity-related functional antibody activity appeared to be significantly shaped by the parasite variant. Prior studies have described variant-specific BIA and OA of naturally acquired antibodies in pregnant women (16,35) although related data assessing these two functions of antibodies in the same samples are absent. Plasma BIA in multigravidae was significantly higher against NF54 parasites, and plasma OA was significantly higher against FCR3 parasites than in primigravidae.…”

Section: Discussionmentioning

confidence: 99%

“…VAR2CSA (ϳ350 kDa), a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, is the immunodominant variant IE surface antigen expressed by placental parasites (12,(16)(17)(18). Several lines of evidence suggest that VAR2CSA is the major surface protein expressed by placental parasites (10,17), the principal ligand for CSA binding (19), and the main target of antibodies acquired during PM (17), supporting this protein as the leading vaccine candidate to prevent PM.…”

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confidence: 99%

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Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

et al. 2019

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During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) accumulate in the intervillous spaces of the placenta by binding to chondroitin sulfate A (CSA) and elicit inflammatory responses that are associated with poor pregnancy outcomes. Primigravidae lack immunity to IE that sequester in the placenta and thus are susceptible to placental malaria (PM). Women become resistant to PM over successive pregnancies as antibodies to placental IE are acquired. Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity and binding inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54). Overall, antibody reactivity to VAR2CSA recombinant proteins and to CSA-binding IE was higher in multigravidae than in primigravidae. However, plasma from Malian gravid women reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies was variant dependent: binding inhibition of P. falciparum strain NF54 (P < 0.001) but not of the strain FCR3 increased significantly with parity, while only opsonizing activity against FCR3 (P < 0.001) increased significantly with parity. In addition, opsonizing and binding inhibition activities of plasma of multigravidae were significantly correlated in assays of FCR3 (r = 0.4, P = 0.01) but not of NF54 isolates; functional activities did not correlate in plasma from primigravidae. These data suggest that IE surface-expressed epitopes involved in each functional activity differ among P. falciparum strains. Consequently, geographic bias in circulating strains may impact antibody functions. Our study has implications for the development of PM vaccines aiming to achieve broad protection against various parasite strains.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

et al. 2019

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“…However, recent findings indicate that broadly neutralising antibodies of multigravidae are not depleted on VAR2CSA recombinant antigens. Using a new approach to assess VAR2CSA domains for functional epitopes recognized by naturally acquired antibodies, Doritchamou et al (2016) recently demonstrated that different Duffy binding-like (DBL) domain-specific IgG could react to both homologous as well as heterologous antigens and parasites, suggesting that conserved epitopes are shared between allelic variants. In addition, IE binding was blocked by ID1-DBL2-ID2a, DBL4 and DBL5-specific IgG, while partial cross-inhibition activity was observed with purified IgG specific to ID1-DBL2-ID2a and DBL4 antigens.…”

Section: Pathologies Other Than Cm: Mipmentioning

confidence: 99%

Severe malaria: what’s new on the pathogenesis front?

Wassmer

Grau

2017

International Journal for Parasitology

111

102

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Plasmodium falciparum causes the most severe and fatal form of malaria in humans with over half a million deaths each year. Cerebral malaria (CM), a complex neurological syndrome of severe falciparum malaria, is often fatal and represents a major public health burden. Despite vigorous efforts, the pathophysiology of CM remains to be elucidated, thereby hindering the development of adjunctive therapies. In recent years, multidisciplinary and collaborative approaches have led to groundbreaking progress both in the laboratory and in the field. Here we review the latest breakthroughs in severe malaria pathogenesis, with a specific focus on new pathogenetic mechanisms leading to CM. The most recent findings point towards specific parasite phenotypes targeting brain microvasculature, endothelial dysfunction and subsequent oedema-induced brain swelling.

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“…Microbes can also induce suppression, blocking [4], impeding [5,6] and many other escape mechanisms [7] rendering new or previously acquired immunity useless.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

TCR-contacting residues orientation and HLA-DRβ* binding preference determine long-lasting protective immunity against malaria

Alba

Suárez

Varela

et al. 2016

Biochemical and Biophysical Research Communications

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VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies toPlasmodium falciparumPlacental Malaria

Abstract: Broadly neutralizing antibodies of multigravidae are not depleted on VAR2CSA recombinant antigens, and hence development of VAR2CSA vaccines based on a single construct and variant might induce antibodies with limited broadly neutralizing activity.

Cited by 36 publications

References 48 publications

Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

Severe malaria: what’s new on the pathogenesis front?

TCR-contacting residues orientation and HLA-DRβ* binding preference determine long-lasting protective immunity against malaria

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