New ways to beat malaria
One of the main problems in fighting malaria is the speed with which Plasmodium falciparum, the causative agent of human malaria, is able to vary its genetic makeup. This allows antigenic variation, which makes the creation of effective vaccines very difficult. Antigenic variability also gives P. falciparum the ability to persist in the face of an immune reaction and to reinfect people who have been previously exposed to the disease. Effective immunity to malaria requires repeated infections and is slow to develop, so children under ten years of age are most susceptible to illness. The entry of malaria parasites into red blood cells during the replication cycle creates two opportunities to evade host immunity. First, infected red blood cells do not induce a CTL response due to their lack of MHC I expression. Second, malaria antigens exposed on the surface of the cell are highly variable. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a key virulence factor which is expressed on the surface of infected erythrocytes and causes the blood cells to stick to the walls of small blood vessels, preventing infected cells from going through the general circulation and to the spleen (see: Giving malaria the slip).
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Red blood cells infected with Plasmodium display immunodominant parasite antigens on their surface. The reason for this is not clear, but it may be to modify the physical properties of the host cells so that they are not trapped and destroyed in the spleen. The expression of the immunodominant surface protein PfEMP1 is also linked to suppression of host interferon-gamma in the early immune response to the parasite, and low interferon-gamma levels may improve parasite survival.
PfEMP1 is in fact a family of cell surface molecules, encoded by approximately 60 var genes. Antigenic variation is controlled by epigenetic factors including monoallelic var transcription in separate domains at the nuclear periphery, differential histones on otherwise identical var genes, and var gene silencing mediated by telomeres (Antigenic variation in Plasmodium falciparum. Annu Rev Microbiol. 2008 62: 445-470).
Targeting the mechanisms responsible for antigen switching could be a promising approach to tackle the malaria parasite without having to deal with phenotypic variation of the surface molecule. The development of specific biological assays that target antigenic variation could uncover crucial mechanisms required for export to the cell surface, repression of the var gene family, or switching to new variants and would allow the screening of drugs which block these essential processes. Plasmodium’s trump card could yet prove to be its undoing.
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Tags: Biology, Genetics, Health, Malaria, Medicine, Microbiology, Parasitology, Podcast, Science
