Molecular aspects of severe malaria

Abstract

Human infections with Plasmodium falciparum may result in severe forms of malaria. The widespread and rapid development of drug resistance in P. falciparum and the resistance of the disease-transmitting mosquitoes to insecticides make it urgent to understand the molecular background of the pathogenesis of malaria to enable the development of novel approaches to combat the disease. This review focuses on the molecular mechanisms of severe malaria caused by the P. falciparum parasite. The nature of severe malaria and the deleterious effects of parasite-derived toxins and host-induced cytokines are introduced. Sequestration, brought about by cytoadherence and rosetting, is linked to severe malaria and is mediated by multiple receptors on the endothelium and red blood cells. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is the ligand responsible for a majority of binding interactions, and the multiply adhesive features of this sticky molecule are presented. Antigenic variation is also a major feature of PfEMP1 and of the surface of the P. falciparum-infected erythrocyte. Possible mechanisms of P. falciparum antigenic variation in asexual stages are further discussed. We conclude this review with a perspective and suggestions of important aspects for future investigations.

FIG. 1

Cytoadherence and rosetting in postcapillary vasculature. P. falciparum-infected RBCs bind to the postcapillary endothelial lines and to noninfected RBCs. Both phenomena are thought to contribute to the occlusion of blood flow and consequent severe disease. Parasite antigens could stimulate IFN-γ and TNF-α release, which upregulates receptor expression (such as ICAM-1) and redistribution (such as CD31) on the endothelium. ICAM-1 is suggested to mediate pRBC rolling on endothelium, while CD36, CD31, and other receptors are responsible for more stable binding. Sequestration could be augmented by the ability of spontaneous rosetting (in situ rosetting) and cytoadherence of the parasite.

FIG. 2

Soluble CD36 binds to FCR3S1.2-infected RBC surface. Fluorescence (Alexa 488; Bioprobe)-labeled soluble CD36 directly binds to the live infected RBC surface.

FIG. 3

General structure of var PfEMP1. The semiconserved DBL-1α domain and CIDR1α are present in all var genes sequenced to date, and they are the most conserved regions among different sequences. Downstream from the first DBL and CIDR domains, there are a variable number of less-conserved DBL structures. A putative transmembrane domain (TM) is followed by the highly conserved acidic terminal sequence (ATS), which is presumably cytoplasmically located.