Abstract
Malaria, a mosquito‐borne infectious disease caused by parasites of the genus Plasmodium continues to be a major health problem worldwide. The unicellular Plasmodium‐parasites have the unique capacity to infect and replicate within host erythrocytes. By expressing variant surface antigens Plasmodium falciparum has evolved to avoid protective immune responses; as a result in endemic areas anti‐malaria immunity develops gradually over many years of multiple and repeated infections. We are studying the role of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed by asexual stages of P. falciparum responsible for the pathogenicity of severe malaria. The immunopathology of falciparum malaria has been linked to cyto‐adhesion of infected erythrocytes to specific host receptors. A greater appreciation of the PfEMP1 molecules important for the development of protective immunity and immunopathology is a prerequisite for the rational discovery and development of a safe and protective anti‐disease malaria vaccine. Here we review the role of ICAM‐1 and EPCR receptor adhering falciparum‐parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of developing a vaccine targeted specifically to prevent this disease.
Highlights
Infection with Plasmodium falciparum parasites causes the most se‐ vere form of malaria that is responsible for essentially all malaria‐ related deaths
We review the role of intercellular adhesion molecule 1 (ICAM‐1) and endothelial protein C receptor (EPCR) receptor adhering falciparum‐parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of devel‐ oping a vaccine targeted to prevent this disease
This is not least so for the tissue, organ, and receptor‐specific adhesion of infected erythrocytes (IEs) that act as major contributors to the pathogenesis of P. falciparum malaria, including the development of severe complications such as ce‐ rebral malaria (CM)
Summary
Infection with Plasmodium falciparum parasites causes the most se‐ vere form of malaria that is responsible for essentially all malaria‐ related deaths. Disruption of the BBB is common in diseases of the central ner‐ vous system.[102] It is a feature of CM,[103] where it is thought to be the result of endothelial inflammation in the brain, caused by accu‐ mulation and sequestration of IEs, leukocytes, and platelets.[85,104,105] Focal loss of the endothelial intercellular junctions that are central to the maintenance of BBB integrity has been observed in vessels containing sequestered IEs.[103,104,106,107,108] The finding of decreased transendothelial resistance and changes in the expression of pro‐ teins that make up these junctions in brain endothelial cells exposed to IEs in vitro is consistent with these observations.[109,110] Numerous parasite and host factors that have been implicated in CM pathology can affect the permeability of the BBB These include hemozoin‐in‐ duced matrix metalloproteases (MMP), angiopoietins, sphingosine‐1‐ phosphate, nitric oxide, platelet‐activating factor, several cytokines (IL‐1α, IL‐1β, IL‐6, TNFα), and a number of other factors.[91,111,112,113,114,115,116,117] As an example, MMP targets structural proteins of the basal lamina (fibronectin, laminin, heparan sulfate) and tight junction proteins (ZO‐1, ZO‐2, claudin‐5), which is known to cause breakdown of tight junctions, increased paracellular leak, and opening of the BBB during ishemic and inflammatory insults. The IEs might thereby interfere with binding of the normal ligand and compromise protec‐ tive APC‐dependent maintenance of the BBB via PAR‐1.13,307,308 The result would be excessive endothelial inflammation, thrombin activa‐ tion, fibrin cross‐linking, platelet activation, upregulation of ICAM‐1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
