Malaria Pathogenesis

Abstract

In the mosquito-human life cycle, the six species of malaria parasites infecting humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale wallickeri, Plasmodium ovale curtisi, Plasmodium malariae, and Plasmodium knowlesi) undergo 10 or more morphological states, replicate from single to 10,000+ cells, and vary in total population from one to many more than 10⁶ organisms. In the human host, only a small number of these morphological stages lead to clinical disease and the vast majority of all malaria-infected patients in the world produce few (if any) symptoms in the human. Human clinical disease (e.g., fever, anemia, coma) is the result of the parasite preprogrammed biology in concert with the human pathophysiological response. Caveats and corollaries that add variation to this host-parasite interaction include parasite genetic diversity of key proteins, coinfections, comorbidities, delays in treatment, human polymorphisms, and environmental determinants.

Figure 1.

A model of the interactions between Plasmodium parasites (predominantly from Plasmodium falciparum, top) and the human endothelium (bottom) is shown. The prominent feature is the P. falciparum erythrocyte membrane protein 1 (PfEMP1) molecules that protrude from the raised knob structures, which in themselves are made of a combination of human and parasite proteins in a tight complex. Surfins, rifins, and stevors from the parasite are also located in the red cell membrane. On the human side, a range of molecules, depending on tissue, are involved infected parasite interactions, including those that are always present on endothelium (e.g., CD36, outside of the brain and on platelets), are present during activation (e.g., intracellular adhesion molecule 1 [ICAM-1]), and are activated during interaction with other molecules (e.g., endothelial protein C receptor [EPCR] and thrombospondin [TSP]). Special tissue situations include chondroitin sulfate (CSA) in the placenta and CR-1 on uninfected red blood cells (which mediates rosette formation).