Cerebral malaria is associated with differential cytoadherence to brain endothelial cells.

Janet Storm,Patricia Phula,Thomas Lavstsen,Christian W Wang,Christopher A Moxon,Tadge Szestak,Ngawina V Chisala,Karl B Seydel,Terrie E Taylor,Jakob S Jespersen,Alister G Craig,Maurice Mbewe

doi:10.15252/emmm.201809164

Abstract

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.

Highlights

Despite the significant reductions in mortality and morbidity of malaria in the last decade, the percentage of patients infected withPlasmodium falciparum that succumb to severe malaria (SM) is not changing (WHO, 2017), with cerebral malaria (CM) contributing to much of the mortality
The two primer sets DBLa2/1.1/1.2/1.4/1.7 and DBLa1.5/1.6/ 1.8, predicted to mainly target CIDRa1 or CIDRb/c/d-containing PfEMP1, respectively, reported higher levels in CM compared to uncomplicated malaria (UM), with relative levels of DBLa2/1.1/1.2/1.4/1.7 markedly higher than DBLa1.5/1.6/1.8 levels
Data from primers targeting C-terminal Duffy binding-like (DBL) domains showed that, median transcript levels were relatively low, var genes encoding intercellular adhesion molecule 1 (ICAM-1)-binding domains of both group A (DBLb1/3-1) and group B (DBLb5) PfEMP1 were found at significantly higher levels in CM versus UM cases, as were transcripts encoding group A DC5, which has been linked to PECAM-1 binding (Berger et al, 2013)

Summary

Introduction

Despite the significant reductions in mortality and morbidity of malaria in the last decade, the percentage of patients infected withPlasmodium falciparum that succumb to severe malaria (SM) is not changing (WHO, 2017), with cerebral malaria (CM) contributing to much of the mortality. What is clear is that the pathogenesis is multifactorial, with a role for the immune response to the Plasmodium infection (Hunt & Grau, 2003; Ioannidis et al, 2014; Dieye et al, 2016; Mandala et al, 2017; Wolf et al, 2017) and obstruction of the microvasculature by sequestration and rosetting (Rowe et al, 2009; Craig et al, 2012; Ponsford et al, 2012; White et al, 2013; Milner et al, 2015), leading to endothelial dysfunction. The major mediator of parasite cytoadherence to endothelium is P. falciparum erythrocyte membrane protein 1 (PfEMP1), a variant surface antigen expressed on knobs on the IE surface and encoded by approximately 60 var genes per parasite genome, with only one PfEMP1 being expressed on the surface of any individual IE (Scherf et al, 2008; Pasternak & Dzikowski, 2009).

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