Host factors that modify Plasmodium falciparum adhesion to endothelial receptors

Almahamoudou Mahamar,Amadou Barry,Moussa B Kanoute,Santara Gaoussou,Michal Fried,Kadidia B Cisse,Sekouba Keita,Bruce Swihart,Benoît Gamain,Patrick E Duffy,Alassane Dicko,Adama B Dembele,Oumar Attaher,Djibrilla Issiaka,Bacary S Diarra

doi:10.1038/s41598-017-14351-7

Abstract

P. falciparum virulence is related to adhesion and sequestration of infected erythrocytes (IE) in deep vascular beds, but the endothelial receptors involved in severe malaria remain unclear. In the largest ever study of clinical isolates, we surveyed adhesion of freshly collected IE from children under 5 years of age in Mali to identify novel vascular receptors, and examined the effects of host age, hemoglobin type, blood group and severe malaria on levels of IE adhesion to a panel of endothelial receptors. Several novel molecules, including integrin α3β1, VE-cadherin, ICAM-2, junctional adhesion molecule-B (JAM-B), laminin, and cellular fibronectin, supported binding of IE from children. Severe malaria was not significantly associated with levels of IE adhesion to any of the 19 receptors. Hemoglobin AC, which reduces severe malaria risk, reduced IE binding to the receptors CD36 and integrin α5β1, while hemoglobin AS did not modify IE adhesion to any receptors. Blood groups A, AB and B significantly reduced IE binding to ICAM-1. Severe malaria risk varies with age, but age significantly impacted the level of IE binding to only a few receptors: IE binding to JAM-B decreased with age, while binding to CD36 and integrin α5β1 significantly increased with age.

Highlights

Adhesion and sequestration of P. falciparum-infected erythrocytes (IE) underlie cerebral malaria[1] and maternal malaria[2]
The analysis of IE binding included 2904 parasite isolates collected from 1089 children aged 1–60 months (mean (SD) 24.9 (15.4)). 59 of the 2904 parasite isolates were collected from 52 children presenting with severe malaria
We examined the effect of host factors that modify the risk of severe malaria on the level of IE binding to a panel of endothelial receptors

Summary

Introduction

Adhesion and sequestration of P. falciparum-infected erythrocytes (IE) underlie cerebral malaria[1] and maternal malaria[2]. Parasite adhesion to the endothelium is mediated by a family of proteins expressed on the surface of infected erythrocytes (IE) named Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)[16]. Occurring red cell variants, such as hemoglobins C and S, modify PfEMP1 expression as well as parasite adhesion to endothelial cells, suggesting a possible mechanism for their protective effects[17]. Recent studies have implicated novel receptors, such as endothelial protein C receptor (EPCR) related to severe malaria in Tanzania[15], and the receptor gC1qR/HABP1/p32 related to seizures in Mozambique[23]. Host genetic factors like hemoglobin AS and AC reduce the risk of severe malaria. In this study we quantified the level of IE adhesion to a panel of endothelial receptors and analyzed the relationship to host risk factors

Methods

Results

Conclusion