Variant surface antigens of Plasmodium chabaudi as a model to study antigenic variation in P. vivax

Plasmodium vivax Malaria can cause severe illness in people. The parasite is thought to stick to tissues and organs resulting in disease. P. vivax is a chronic infection resulting in low levels of parasites in blood for a long time. One reason for this is that the parasite avoids the host?s antibody response. The malaria parasite lives for much of its life in red blood cells (RBC), and should be invisible to host antibodies. However, the parasite needs to communicate with the environment outside the RBC, and therefore produces molecules present on the RBC surface for this. This means that the parasite is no longer invisible and can be eliminated by antibodies. To avoid this, the proteins at the RBC surface constantly change by switching on and off genes that code for different variants, so that the parasite stays one step ahead of the antibody response. We will use a mouse model of malaria to investigate how the expression of these proteins is regulated, whether they are recognized by antibodies, and whether they are responsible for adhesion in organs. It might possible to use this knowledge to prevent adhesion and thus disease, and to develop vaccines.

Plasmodium vivax is the most widely distributed human malaria. Although considered benign, P. vivax causes anemia, respiratory distress and organ-specific morbidity, the pathogenesis of which is little understood. Infected erythrocytes containing P.vivax parasites cytoadhere, which may contribute to severe pathology and/or aid immune evasion. These aspects are difficult to study as P. vivax cannot grow in vitro and it does not infect tractable animal models. However the parasite shares many features with rodent malarias, most particularly multigene families, which, based on knowledge of P. falciparum, may encode variant antigens expressed on the infected erythrocyte surface involved in adhesion. The pir genes comprise one such shared family, making it possible to investigate the role of these proteins in vivo. We propose to investigate the function and role in immune evasion of pir/PIR in a blood stage infection of Plasmodium chabaudi in mice. This parasite causes chronic infections, undergoes antigenic variation, and sequesters. We will use microarrays and proteomics to determine which genes are transcribed in bloodstages. Transfection approaches will be used to overexpress and silence pirs in order to determine their function in adhesion to endothelium and in the spleen. We will evaluate whether PIR are targets of natural immunity and whether host immune status impacts on PIR expression. Finally, we will use a range of genetically modified parasites constitutively expressing a specific PIR to determine whether PIR is the target of protective immune responses.