<i>P</i><i>lasmodium falciparum</i>adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor

Sampath, Sowmya; Brazier, Andrew J.; Avril, Marion; Bernabeu, Maria; Вигдорович, В. И.; Mascarenhas, Anjali; Gomes, Edwin; Sather, D. Noah; Esmon, Charles T.; Smith, Joseph D.

doi:10.1111/cmi.12478

Cited by 42 publications

(72 citation statements)

References 37 publications

(106 reference statements)

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“…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). Finally, in regions where malaria is endemic, IgG to EPCR-binding CIDR␣1 domains is acquired early in life and before antibodies to other classes of CIDR domains are acquired (54).…”

Section: Figmentioning

confidence: 75%

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: Figmentioning

confidence: 75%

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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“…4B). However, all of the DC8 domains expressed by SM isolates competed less effectively for the APC-EPCR interaction than a positive control, group A variant (IT4var07 CIDRα1.4 domain), which strongly blocks the APC-EPCR interaction (25,26,28).…”

Section: Dc8 Cidrα1 Domains Expressed By Sm Isolates Inhibit the Apc-mentioning

confidence: 92%

“…DC8 CIDRα1 differ in sequence, binding affinity, and ability to inhibit the APC-EPCR interaction (25,27,28), but there have been no in-depth functional characterizations of DC8 CIDRα1 from SM isolates. To perform a deeper phenotypic characterization of DC8 variants in severe isolates, we amplified and sequenced the full-length DC8 CIDRα1 domain (Fig.…”

Section: Dc8 Cidrα1 Domains Expressed By Sm Isolates Inhibit the Apc-mentioning

confidence: 99%

“…EPCR binding involves infected erythrocyte adhesion to vascular endothelial cells (23). The important role of the EPCR-activated protein C (APC) pathway in regulating coagulation, inflammation, and endothelial barrier properties (24) has led to the hypothesis that EPCR-binding parasites may drive pathogenic mechanisms by inhibiting the APC-EPCR interaction (23,(25)(26)(27)(28), thus increasing vascular dysfunction and permeability. Indeed, cerebral swelling is a major risk factor for pediatric death (29) and there is loss of EPCR and fibrin depositions at sites of cerebral sequestration in pediatric autopsies (30).…”

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Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Bernabeu

Danziger

Avril

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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127

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The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/ PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6-and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence. malaria | Plasmodium falciparum | var | PfEMP1 | EPCR

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“…Additional studies have suggested that other CIDRa1.1 and CIDRa1.4 domains, not previously characterized by crystallography, can also bind EPCR in subtly different conformations. 96 Collectively, therefore, CIDRa1 domains share a largely conserved EPCR-binding mechanism, but sequence-specific differences between PfEMP1 subtypes may confer subtle modifications to binding site and affinity with the potential to mediate divergent effects on EPCR function. 97 PfEMP binding to EPCR appears to contribute to malaria pathogenesis beyond IE cytoadherence.…”

Section: Malaria and The Protein C Pathwaymentioning

confidence: 99%

Emerging roles for hemostatic dysfunction in malaria pathogenesis

O’Sullivan

Preston

O’Regan

et al. 2016

Blood

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Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum–infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

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Plasmodium falciparumadhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor

Cited by 42 publications

References 37 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

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

Emerging roles for hemostatic dysfunction in malaria pathogenesis

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