Expression of the Domain Cassette 8 Plasmodium falciparum Erythrocyte Membrane Protein 1 Is Associated with Cerebral Malaria in Benin

Bertin, Gwladys; Lavstsen, Thomas; Guilhot, François; Doritchamou, Justin; Wang, Christian W.; Jespersen, Jakob S.; Ezimegnon, Sem; Fiévet, Nadine; Alao, Maroufou Jules; Lalya, Francis; Massougbodji, Achille; Ndam, Nicaise Tuikue; Theander, Thor G.; Deloron, Philippe

doi:10.1371/journal.pone.0068368

Cited by 59 publications

(70 citation statements)

References 29 publications

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“…In line with previously reported observations (25,26,39), DC8 and group A PfEMP1 were highly expressed in most hospitalized children, and the abundance of transcripts encoding DC8 PfEMP1 was statistically significantly higher in patients with severe malaria than in those with uncomplicated disease. In contrast to data from previous reports, the difference in the abundances of transcripts encoding DC13 (containing CIDR␣1.4) in patients with severe malaria or uncomplicated disease did not reach statistical significance.…”

Section: Figsupporting

confidence: 92%

“…Data from this study in combination with previously reported observations from other studies of var transcription (25,26,29,31) suggest that the expression of EPCR-binding PfEMP1 is the overarching parasite phenotype associated with the development of symptomatic and severe malaria and that its clinical relevance is stable across various confounding host or environmental factors. In line with this are the observations that parasites from children with severe disease and in vitro-adapted parasites expressing CIDR␣1 PfEMP1 bind endothelial cells via EPCR (22,(52)(53)(54) and that CIDR␣1 domains bind EPCR with high affinity, and binding inhibits the ability of EPCR to bind protein C, thereby potentially driving pathogenic endothelial inflammation (27,28,(55)(56)(57).…”

Section: Figsupporting

confidence: 74%

“…Bars represent transcript levels reported by primer sets CIDRa1.1 (C1) (red), CIDRa1.8 (C8) (orange), CIDRa1.4/6a (c4) (blue), CIDRa1.5 (C5) (black), CIDRa1.6b (C6) (gray), and CIDRa1.7 (c7) (green). The red line indicates a T u value of 16. of malaria patients and a broader spectrum of disease outcomes than in previous studies employing qPCR (25,26,31). Patient groups included children with parasitemia without fever, children with mild malaria who could be treated in the village, children who required hospitalization, children with severe disease manifestations, and children with a fatal infection outcome.…”

Section: Figmentioning

confidence: 99%

“…Here, we show by quantitative PCR (qPCR) and by using a new set of var typespecific primers that is more comprehensive than those used previously (25,26) that parasites from Tanzanian children hospitalized with malaria and diagnosed with severe malarial anemia, cerebral malaria, or no severe complications (uncomplicated malaria) were all characterized by high transcript levels of var genes encoding DC8 and the subset of group A var genes encoding EPCR-binding PfEMP1. Furthermore, in a few cases, severe disease was associated with increased levels of transcripts encoding specific subsets of DBL␤ or DBL domains.…”

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The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

et al. 2017

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By attaching infected erythrocytes to the vascular lining, Plasmodium falciparum parasites leave blood circulation and avoid splenic clearance. This sequestration is central to pathogenesis. Severe malaria is associated with parasites expressing an antigenically distinct P. falciparum erythrocyte membrane protein 1 (PfEMP1) subset mediating binding to endothelial receptors. Previous studies indicate that PfEMP1 adhesins with so-called CIDR␣1 domains capable of binding endothelial protein C receptor (EPCR) constitute the PfEMP1 subset associated with severe pediatric malaria. To analyze the relative importance of different subtypes of CIDR␣1 domains, we compared Pfemp1 transcript levels in children with severe malaria (including 9 fatal and 114 surviving cases), children hospitalized with uncomplicated malaria (n ϭ 42), children with mild malaria not requiring hospitalization (n ϭ 10), and children with parasitemia and no ongoing fever (n ϭ 12). High levels of transcripts encoding EPCR-binding PfEMP1 were found in patients with symptomatic infections, and the abundance of these transcripts increased with disease severity. The compositions of CIDR␣1 subtype transcripts varied markedly between patients, and none of the subtypes were dominant. Transcript-level analyses targeting other domain types indicated that subtypes of DBL␤ or DBL domains might mediate binding phenomena that, in conjunction with EPCR binding, could contribute to pathogenesis. These observations strengthen the rationale for targeting the PfEMP1-EPCR interaction by vaccines and adjunctive therapies. Interventions should target EPCR binding of all CIDR␣1 subtypes. KEYWORDS Plasmodium falciparum, antigenic variation, gene expression, malaria, PfEMP1 B ased on simple clinical observations, malaria patients can be divided into a smaller group with severe manifestations and a much larger group with uncomplicated disease (1). In areas of Africa with high to moderate rates of malaria transmission, severe malaria is seen almost only in children below 5 years of age (2). At the first entry point for health care, the majority of African children diagnosed with Plasmodium falciparum malaria suffer from uncomplicated febrile disease and are treated as outpatients. Downloaded fromHowever, based on the initial assessment, the examining physician hospitalizes some patients with more manifest symptoms. These children are not well, but based on simple triage, they can be further divided into a large group with uncomplicated disease, who, upon correct treatment, will be very likely to survive the disease, and a smaller group with severe disease, where a proportion will die despite the administration of what is currently considered optimal care (3). It is estimated that around 10 million children suffer from severe malaria every year and that 5 to 10% of these children die (4). Even though most children in areas where malaria is endemic are expected to experience several bouts of malaria during childhood, only one to three of these bouts are likely to ca...

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Section: Figsupporting

confidence: 92%

Section: Figsupporting

confidence: 74%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

et al. 2017

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“…If this is true, it should be possible to protect children against severe malaria by inducing cross-reactive IgG by vaccination of infants. Analyses of var gene transcription and PfEMP1 expression in children suffering from severe malaria has indicated that parasites causing severe disease express a group of PfEMP1s binding endothelial protein C receptor (EPCR) (24)(25)(26)(27)(28). The binding is mediated by N-terminal CIDR domains, and only PfEMP1s containing CIDR domains of the subtypes ␣1.1 or ␣1.4 to ␣1.8 bind EPCR (29).…”

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IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

et al. 2015

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bSevere malaria syndromes are precipitated by Plasmodium falciparum parasites binding to endothelial receptors on the vascular lining. This binding is mediated by members of the highly variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We have previously identified a subset of PfEMP1 proteins associated with severe malaria and found that the receptor for these PfEMP1 variants is endothelial protein C receptor (EPCR). The binding is mediated through the amino-terminal cysteinerich interdomain region (CIDR) of the subtypes ␣1.1 and ␣1.4 to ␣1.8. In this study, we investigated the acquisition of anti-CIDR antibodies using plasma samples collected in four study villages with different malaria transmission intensities in northeastern Tanzania during a period with a decline in malaria transmission. We show that individuals exposed to high levels of malaria transmission acquire antibodies to EPCR-binding CIDR domains early in life and that these antibodies are acquired more rapidly than antibodies to other CIDR domains. The rate by which antibodies to EPCR-binding CIDR domains are acquired in populations in areas where malaria is endemic is determined by the malaria transmission intensity, and on a population level, the antibodies are rapidly lost if transmission is interrupted. This indicates that sustained exposure is required to maintain the production of the antibodies. Individuals in countries where malaria is endemic acquire immunity to febrile malaria episodes after years of exposure and repeated disease episodes (1, 2). The age at which protection is established depends on the malaria transmission intensity in the area of residence (3-6). Immunoglobulin G (IgG) targeting the asexual blood stages of the parasites is an important immunological effector mechanism mediating malaria immunity (7,8), and several lines of evidence indicate that members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) protein family are important targets for immunity (6, 9-13). PfEMP1s are large multidomain proteins consisting of two to nine Duffy binding-like (DBL) and cysteine-rich interdomain region (CIDR) domains, which based on sequence similarity can be divided into different subgroups (14, 15). The proteins are expressed on the surface of infected erythrocytes and mediate binding of these cells to receptors on the vascular lining (16)(17)(18)(19). In this way, the infected erythrocytes are effectively sequestered, and they avoid splenic clearance. IgG recognizing PfEMP1 inhibits the binding between the infected erythrocytes and the endothelial cells, and parasites expressing a PfEMP1 targeted by binding inhibitory IgG will be killed in the spleen. However, in an evolutionary arms race each parasite genome has acquired about 60 var genes, encoding different PfEMP1s binding different endothelial receptors (20), and isogenic parasites can, depending on which PfEMP1 they express, bind different endothelial receptors. To multiply effectively, parasites are limited to expressing PfEMP1 types not t...

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Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

et al. 2017

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Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.

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Expression of the Domain Cassette 8 Plasmodium falciparum Erythrocyte Membrane Protein 1 Is Associated with Cerebral Malaria in Benin

Cited by 59 publications

References 29 publications

The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

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