Diverse functional outcomes of<i>P</i><i>lasmodium falciparum</i>ligation of EPCR: potential implications for malarial pathogenesis

Gillrie, Mark R.; Avril, Marion; Brazier, Andrew J.; Davis, Shevaun P.; Stins, Monique F.; Smith, Joseph D.; Ho, May

doi:10.1111/cmi.12479

Cited by 51 publications

(65 citation statements)

References 39 publications

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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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“…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. Recent in vitro studies indicate that PfEMP binding to EPCR limits protein C activation, EPCR-dependent PAR1 activation, and PAR1-dependent protection of the EC barrier integrity.…”

Section: Malaria and The Protein C Pathwaymentioning

confidence: 99%

“…Recent in vitro studies indicate that PfEMP binding to EPCR limits protein C activation, EPCR-dependent PAR1 activation, and PAR1-dependent protection of the EC barrier integrity. 97,98 Consequently, PfEMP1 binding would be predicted to severely attenuate normal protein C pathway activity during P falciparum infection. In addition, the significant proinflammatory response associated with severe malaria is likely to induce further protein C pathway dysfunction.…”

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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“…55,71,72 As APC exerts a protective effect on thrombin induced barrier dysfunction, IRBC adhesion may exaggerate the barrier dysfunction elicited by thrombin. 71,73,74 It should be emphasized that the in vitro evidence for the disruption of barrier function as a direct effect of cytoadherence is not robust, as each process has been demonstrated by only a few IRBC, or by using surrogates, such as antibody or recombinant PfEMP1-coated beads. It is conceivable that the number of interactions could be much higher in vivo, in view of the fact that microvessels are densely packed with IRBC ( Fig.…”

Section: Cytoadherencementioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

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Diverse functional outcomes ofPlasmodium falciparumligation of EPCR: potential implications for malarial pathogenesis

Cited by 51 publications

References 39 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

Emerging roles for hemostatic dysfunction in malaria pathogenesis

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

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