Malaria: modification of the red blood cell and consequences in the human host

Abstract

Residence in the human erythrocyte is essential for the lifecycle of all Plasmodium that infect man. It is also the phase of the life cycle that causes disease. Although the red blood cell (RBC) is a highly specialized cell for its function of carrying oxygen to and carbon dioxide away from tissues, it is devoid of organelles and lacks any cellular machinery to synthesize new protein. Therefore in order to be able to survive and multiply within the RBC membrane the parasite needs to make many modifications to the infected RBC (iRBC). Plasmodium falciparum (P. falciparum) also expresses parasite-derived proteins on the surface of the iRBC that enable the parasite to cytoadhere to endothelial and other intravascular cells. These RBC modifications are at the root of malaria pathogenesis and, in this ancient disease of man, have formed the epicentre of a genetic 'battle' between parasite and host. This review discusses some of the critical modifications of the RBC by the parasite and some of the consequences of these adaptations on disease in the human host, with an emphasis on advances in understanding of the pathogenesis of severe and cerebral malaria (CM) from recent research.

Keywords: P. falciparum; PfEMP1; RBC polymorphisms; cerebral malaria; sequestration.

Fig 1

Scanning electron micrograph of normal RBC and Plasmodium falciparum iRBC. The three normal RBC at the centre appear regular and smooth and have a biconcave structure. In contrast the two peripheral iRBC have an irregular and rough surface and have lost the biconcave structure. (Published with permission, Professor David Ferguson, Oxford University, Oxford, UK). Scale bar = 1 μm.

Fig 2

Direct and indirect effects of iRBC on microvascular endothelial cells. In addition to their capacity to directly alter endothelial cells, iRBC and the microparticles they release can trigger potent pro-inflammatory responses, notably by the activation of host leucocytes. These activated cells are responsible for an overproduction of mediators, including cytokines. In turn, cytokine effects can be amplified by platelets. Both platelet-derived and endothelial-derived microparticles also participate in microvascular damage. See text for details. iRBC: infected red blood cell; RMP: red blood cell microparticles; PMP platelet microparticles; EMP endothelial microparticles; BBB, blood-brain barrier.