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

Bernabeu, Maria; Danziger, Samuel A.; Avril, Marion; Vaz, Marina; Babar, Prasad H.; Brazier, Andrew J.; Herricks, Thurston; Maki, Jennifer; Pereira, Ligia; Mascarenhas, Anjali; Gomes, Edwin; Chéry, Lisly; Aitchison, John D.; Rathod, Pradipsinh K.; Smith, Joseph D.

doi:10.1073/pnas.1524294113

Cited by 95 publications

(146 citation statements)

References 61 publications

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“…Thus, EPCR binding by CIDR␣1 domains appears to be required for the development of severe symptoms, but ICAM-1 binding and other host receptor interactions may, in some individuals (41), act in concert to strengthen cytoadhesion and aggravate disease. It is conceivable that this notion also explains the inconsistent association of the expression of diverse DBL variants with both uncomplicated (DBL4) (25) and severe (DBL2a and DBL3) (this study) pediatric malaria and severe malaria in adults (DBL5) (31).…”

Section: Figmentioning

confidence: 81%

“…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%

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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: Figmentioning

confidence: 81%

Section: Figmentioning

confidence: 99%

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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“…70 Moreover, a subset of parasites from patients with CM has been shown to bind to EPCR, and may compete with APC for the binding to this receptor. 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.…”

Section: Cytoadherencementioning

confidence: 99%

“…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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“…While expression of EPCR-binding PfEMP1s has been associated with all forms of severe malaria [16,[38][39][40][41], probably due to broad tissue tropism, efficient sequestration and the proposed pathogenic consequences of receptor binding, it is not specially linked to the development of cerebral disease. A particular association with cerebral symptoms was found for parasites expressing PfEMP1s that combine both an EPCR-binding CIDRα1 domain and a DBLβ domain that can bind to ICAM-1, allowing simultaneous binding of infected erythrocytes to both ligands [38,42,43] (Figure 1).…”

Section: Do Anti-disease Immunogens Have a Place In Future Malaria Vamentioning

confidence: 99%

Towards an anti-disease malaria vaccine

Lennartz

Lavstsen

Higgins

2017

Emerging Topics in Life Sciences

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Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

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

Cited by 95 publications

References 61 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

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Towards an anti-disease malaria vaccine

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