Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates

Kraemer, Susan M.; Kyes, Sue; Aggarwal, Gautam; Springer, Amy L.; Nelson, Siri; Christodoulou, Zóe; Smith, Leia M.; Wang, Ke; Levin, Emily; Newbold, Chris; Myler, Peter J.; Smith, Joseph D.

doi:10.1186/1471-2164-8-45

Cited by 172 publications

(205 citation statements)

References 76 publications

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“…Recently, the var gene repertoire was obtained from the FCR3/CS2/IT4 parasite genotype [27]. To identify the var gene(s) predominantly transcribed in the 1F1-CD36 and 1F1-BeWo parasite populations, gene-specific primers were designed to the 56 known var genes (materials and methods) and quantitative real-time PCR was performed on RNA extracted from ring stage parasites at 10 h post-invasion (Fig.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Var2csa Gene Impairs Placental Malaria Associated Adhesion Phenotype

et al. 2007

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Infection with Plasmodium falciparum during pregnancy is one of the major causes of malaria related morbidity and mortality in newborn and mothers. The complications of pregnancy-associated malaria result mainly from massive adhesion of Plasmodium falciparum-infected erythrocytes (IE) to chondroitin sulfate A (CSA) present in the placental intervillous blood spaces. Var2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is the predominant parasite ligand mediating CSA binding. However, experimental evidence suggests that other host receptors, such as hyaluronic acid (HA) and the neonatal Fc receptor, may also support placental binding. Here we used parasites in which var2csa was genetically disrupted to evaluate the contribution of these receptors to placental sequestration and to identify additional adhesion receptors that may be involved in pregnancy-associated malaria. By comparison to the wild-type parasites, the FCR3Δvar2csa mutants could not be selected for HA adhesion, indicating that var2csa is not only essential for IE cytoadhesion to the placental receptor CSA, but also to HA. However, further studies using different pure sources of HA revealed that the previously observed binding results from CSA contamination in the bovine vitreous humor HA preparation. To identify CSA-independent placental interactions, FCR3Δvar2csa mutant parasites were selected for adhesion to the human placental trophoblastic BeWo cell line. BeWo selected parasites revealed a multi-phenotypic adhesion population expressing multiple var genes. However, these parasites did not cytoadhere specifically to the syncytiotrophoblast lining of placental cryosections and were not recognized by sera from malaria-exposed women in a parity dependent manner, indicating that the surface molecules present on the surface of the BeWo selected population are not specifically expressed during the course of pregnancy-associated malaria. Taken together, these results demonstrate that the placental malaria associated phenotype can not be restored in FCR3Δvar2csa mutant parasites and highlight the key role of var2CSA in pregnancy malaria pathogenesis and for vaccine development.

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Section: Resultsmentioning

confidence: 99%

Disruption of Var2csa Gene Impairs Placental Malaria Associated Adhesion Phenotype

et al. 2007

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“…Within this cohort, we compared antibody levels and memory B-cell frequencies specific for a parasite protein that is expressed only during pregnancy to those for similar antigens not restricted in this way. More specifically, we compared responses to the VAR2CSA-type P. falciparum EMP1 (PfEMP1) protein IT4VAR04 (19) and responses specific for two other PfEMP1 proteins, HB3VAR06 (20) and IT4VAR60 (also known as PARϩ or FCR3S1.2VAR2) (21). The PfEMP1 proteins constitute an ϳ60-member family of clonally variant P. falciparum antigens that are expressed in a mutually exclusive manner on the surfaces of P. falciparum-infected erythrocytes (IEs), where they act as ligands for a range of host receptors in the vasculature (22)(23)(24)(25).…”

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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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“…However, we feel this is a good approximation, as strong structural similarities mediated by conserved regions of DNA have been shown to exist between PfEMP1 variants and are predicted to mediate cross-reactivity of certain epitopes (71), protein structure has played a significant part in how var genes have been classified, suggesting a strong link between sequence and structure (3,4,44), and some functional differences have been observed between groups (43, 72), suggesting that variant proteins are more similar within groups than across groups and are targeted similarly by the immune system, increasing the likelihood of cross-reactive responses. In addition, our analysis of sequence similarity generated patterns that would be expected based on the extracellular domain structure, and the results were similar when we looked only at a single domain.…”

Section: Discussionmentioning

confidence: 93%

“…Predicted protein sequences were obtained from PlasmoDB (http://www.plasmodb.org) for 62 var genes in the 3D7 reference strain (44), which has been shown to be representative of typical sequence diversity across both regions and strains (45). The sequences were then aligned and an identity matrix calculated using Clustal X2 (46).…”

Section: Methodsmentioning

confidence: 99%

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

et al. 2014

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The within-host dynamics of an infection with the malaria parasite Plasmodium falciparum are the result of a complex interplay between the host immune system and parasite. Continual variation of the P. falciparum erythrocyte membrane protein (PfEMP1) antigens displayed on the surface of infected red blood cells enables the parasite to evade the immune system and prolong infection. Despite the importance of antigenic variation in generating the dynamics of infection, our understanding of the mechanisms by which antigenic variation generates long-term chronic infections is still limited. We developed a model to examine the role of cross-reactivity in generating infection dynamics that are comparable to those of experimental infections. The hybrid computational model we developed is attuned to the biology of malaria by mixing discrete replication events, which mimics the synchrony of parasite replication and invasion, with continuous interaction with the immune system. Using simulations, we evaluated the dynamics of a single malaria infection over time. We then examined three major mechanisms by which the dynamics of a malaria infection can be structured: cross-reactivity of the immune response to PfEMP1, differences in parasite clearance rates, and heterogeneity in the rate at which antigens switch. The results of our simulations demonstrate that cross-reactive immune responses play a primary role in generating the dynamics observed in experimentally untreated infections and in lengthening the period of infection. Importantly, we also find that it is the primary response to the initially expressed PfEMP1, or small subset thereof, that structures the cascading cross-immune dynamics and allows for elongation of the infection.

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Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates

Cited by 172 publications

References 76 publications

Disruption of Var2csa Gene Impairs Placental Malaria Associated Adhesion Phenotype

Disruption of Var2csa Gene Impairs Placental Malaria Associated Adhesion Phenotype

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

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

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