Investigating the function of Fc-specific binding of IgM toPlasmodium falciparumerythrocyte membrane protein 1 mediating erythrocyte rosetting

Stevenson, Liz; Huda, Pie; Jeppesen, Anine; Laursen, Erik; Rowe, J. Alexandra; Craig, Alister G.; Streicher, Werner; Barfod, Lea; Hviid, Lars

doi:10.1111/cmi.12403

Cited by 55 publications

(100 citation statements)

References 81 publications

(132 reference statements)

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“…This was also the case for transcripts encoding group A non-EPCR-binding domains and the ICAM-1-binding domains DBLb1/3-1 (group A) and DBLb5 (group B), all in line with previous reports (Lavstsen et al, 2012;Bertin et al, 2013;Bernabeu et al, 2016;Kessler et al, 2017;Mkumbaye et al, 2017;Shabani et al, 2017). The functions of the C-terminal DBLe and DBLf domains are not fully understood, but some are involved in non-immune IgM and a 2 -macroglobulin binding (Semblat et al, 2006(Semblat et al, , 2015Jeppesen et al, 2015;Stevenson et al, 2015a;Pleass et al, 2016). This may be attributed to the inclusion of retinopathy in our CM cases, producing more definitive case definition.…”

Section: Discussionsupporting

confidence: 87%

“…Higher transcripts of the DBLf2a, DBLf2c, DBLf3, DBLf5 and DBLe2 domains were detected in the CM cases, of which DBLf2a, DBLf3 and DBLe2 were also reported in a recent study (Kessler et al, 2017;Mkumbaye et al, 2017). The functions of the C-terminal DBLe and DBLf domains are not fully understood, but some are involved in non-immune IgM and a 2 -macroglobulin binding (Semblat et al, 2006(Semblat et al, , 2015Jeppesen et al, 2015;Stevenson et al, 2015a;Pleass et al, 2016). The variant nature of var genes makes it difficult to design qPCR primers with high enough specificity and selectivity to cover transcripts encoding CD36-binding CIDR domains (group B and C var genes).…”

Section: Discussionmentioning

confidence: 82%

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Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

et al. 2019

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Sequestration of Plasmodium falciparum‐infected erythrocytes (IE) within the brain microvasculature is a hallmark of cerebral malaria (CM). Using a microchannel flow adhesion assay with TNF‐activated primary human microvascular endothelial cells, we demonstrate that IE isolated from Malawian paediatric CM cases showed increased binding to brain microvascular endothelial cells compared to IE from uncomplicated malaria (UM) cases. Further, UM isolates showed significantly greater adhesion to dermal than to brain microvascular endothelial cells. The major mediator of parasite adhesion is P. falciparum erythrocyte membrane protein 1, encoded by var genes. Higher levels of var gene transcripts predicted to bind host endothelial protein C receptor (EPCR) and ICAM‐1 were detected in CM isolates. These data provide further evidence for differential tissue binding in severe and uncomplicated malaria syndromes, and give additional support to the hypothesis that CM pathology is based on increased cytoadherence of IE in the brain microvasculature.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 82%

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

et al. 2019

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“…Additionally, a C-terminal DBLε2 domain was a top var feature in the retinopathy and swelling models, but it was not elevated in all patients. Notably, the DBLε2 domain binds to human IgM (Jeppesen et al, 2015), an adhesion property that can strengthen pRBC binding affinity (Akhouri et al, 2016; Stevenson et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

Kessler

Dankwa

Bernabeu

et al. 2017

Cell Host & Microbe

100

133

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Summary Brain swelling is the major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR) binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.

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“…PECAM1 binding (Treutiger et al , ) has been associated with PfEMP1 containing DC5 (Berger et al , ), but var transcripts encoding DC5 PfEMP1 were not found in high abundance in the studied children. Binding to IgM (Semblat et al , , ; Stevenson et al , ) and alpha‐2‐macroglobulin (Stevenson et al , ) has been mapped to C‐terminal PfEMP1 domains, DBLε and/or DBLζ, which exhibited higher transcript proportions in children with uncomplicated malaria (Fig EV1).…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

et al. 2016

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Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR‐binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full‐length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1‐EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction.

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Investigating the function of F_c-specific binding of IgM toPlasmodium falciparumerythrocyte membrane protein 1 mediating erythrocyte rosetting

Cited by 55 publications

References 81 publications

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

Plasmodium falciparum var genes expressed in children with severe malaria encode CIDR α1 domains

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