Antibodies among Men and Children to Placental-Binding Plasmodium falciparum-Infected Erythrocytes that Express var2csa

Beeson, James G.; Ndungu, Francis M.; Persson, Kristina; Chesson, Joanne M.; Kelly, G; Uyoga, Sophie; Hallamore, S; Williams, Thomas N.; Reeder, John C.; Brown, Graham V.; Marsh, Kevin

doi:10.4269/ajtmh.2007.77.22

Cited by 47 publications

(55 citation statements)

References 49 publications

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“…However, the level and prevalence of the antibodies observed in those studies were lower in men and children than in exposed multigravid women (24). From proteomic studies, VAR2CSA was detected in parasites of nonplacental origin (43), and in another study, parasites from nonpregnant hosts could bind to CSA (24,44). Consistent with our study, widespread DBL5ε reactivity was observed in plasma from Tanzanian children, suggesting that VAR2CSA in nonpregnant populations could share specific epitopes with VAR2CSA from placental parasites (25).…”

Section: Discussionsupporting

confidence: 76%

“…Moreover, these antibodies can inhibit parasite adhesion to CSA in vitro. It was reported in previous studies that antibodies against VAR2CSA are not exclusively restricted to pregnancy (24,25). However, the level and prevalence of the antibodies observed in those studies were lower in men and children than in exposed multigravid women (24).…”

Section: Discussionmentioning

confidence: 48%

“…It was reported in previous studies that antibodies against VAR2CSA are not exclusively restricted to pregnancy (24,25). However, the level and prevalence of the antibodies observed in those studies were lower in men and children than in exposed multigravid women (24). From proteomic studies, VAR2CSA was detected in parasites of nonplacental origin (43), and in another study, parasites from nonpregnant hosts could bind to CSA (24,44).…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, naturally acquired antibodies to VAR2CSA can efficiently block IE adhesion to CSA (22,23). These antibodies are occasionally detected in nonpregnant patients (24,25); however, the prevalence and levels of anti-VAR2CSA antibodies are much lower than in pregnant women from the same region (24).…”

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confidence: 99%

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Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

et al. 2014

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iIn pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum. Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. However, in Colombia, we detected antibodies against multiple constructs of VAR2CSA among men and children with acute P. falciparum and Plasmodium vivax infection. The majority of men and children (>60%) had high levels of IgGs against three recombinant domains of VAR2CSA: DBL5, DBL3X, and ID1-ID2. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P. falciparum or to P. vivax. Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P. falciparum or P. vivax infection outside pregnancy. These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

et al. 2014

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“…Apart from the trivial explanation of unrecognized or unremembered (unsuccessful) pregnancies mentioned above, it remains a possibility that VAR2CSA-specific immunity can occasionally appear independent of pregnancy. Indeed, there are a few reports of significant levels of IgG to VAR2CSA-type PfEMP1 among P. falciparum-exposed men and children (73). However, the strong link between parity and susceptibility to placental malaria suggests that pregnancy-independent immune responses to VAR2CSA-type PfEMP1 do not normally protect against placental malaria.…”

Section: Discussionmentioning

confidence: 99%

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

et al. 2014

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Protective immunity to Plasmodium falciparum malaria acquired after natural exposure is largely antibody mediated. IgG-specific P. falciparum EMP1 (PfEMP1) proteins on the infected erythrocyte surface are particularly important. The transient antibody responses and the slowly acquired protective immunity probably reflect the clonal antigenic variation and allelic polymorphism of PfEMP1. However, it is likely that other immune-evasive mechanisms are also involved, such as interference with formation and maintenance of immunological memory. We measured PfEMP1-specific antibody levels by enzyme-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods (pregnancy) to responses specific for comparable antigens expressed independent of pregnancy. Our data indicate that PfEMP1-specific B-cell memory is adequately acquired even when antigen exposure is infrequent (e.g., VAR2CSA-type PfEMP1). Furthermore, immunological memory specific for VAR2CSA-type PfEMP1 can be maintained for many years without antigen reexposure and after circulating antigen-specific IgG has disappeared. The study provides evidence that natural exposure to P. falciparum leads to formation of durable B-cell immunity to clinically important PfEMP1 antigens. This has encouraging implications for current efforts to develop PfEMP1-based vaccines. P rotective immunity to Plasmodium falciparum malaria acquired after natural exposure is mediated to a large extent by IgG antibodies targeting the asexual blood stages of the parasites (reviewed in reference 1). The low rate of acquisition probably reflects the extensive clonal antigenic variation and allelic polymorphism of key antigens. However, other immune-evasive mechanisms may also be involved, such as interference with formation and maintenance of immunological memory. Indeed, it has often been speculated that such subversion is important for the slow and incomplete acquisition of clinical protection following natural exposure to P. falciparum in areas where these parasites are stably transmitted (reviewed in references 2, 3, and 4). The evidence supporting the hypothesis of a fragile or dysfunctional immunological memory to P. falciparum includes the often transient IgG responses in children with malaria (5-9), apparent interference with antigen presentation (10, 11), "masking" of surface-exposed IgG epitopes (12), and expansion of "atypical" or "exhausted" B cells after prolonged exposure to P. falciparum antigens (13,14). Conversely, the hypothe...

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Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration

Agerbæk

Pereira

Clausen

et al. 2017

Intl Journal of Cancer

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Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. OfCS is absent from other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor-site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue, encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy.

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Antibodies among Men and Children to Placental-Binding Plasmodium falciparum-Infected Erythrocytes that Express var2csa

Cited by 47 publications

References 49 publications

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration

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