This application is designed to address the molecular basis of malaria-associated anemia, one of the mostprevalent and often life-threatening manifestations of infection with the malaria parasite. Hundreds of millionsof people have clinical malaria infections every year and thus the impact of the disease on human health isprofound. During the process by which the parasites invade erythrocytes to allow them to multiply within,parasite molecules bind to the surface of these cells. It is proposed that these molecules, which are alsoshed from the parasite, bind to uninfected erythrocytes in the infected host and promote the destruction andclearance of uninfected red blood cells, thus contributing to anemia. Furthermore it is proposed to test thehypothesis that specific antibodies to such molecules promote this clearance. Two molecular complexesconsisting of abundant proteins that have been implicated in binding to host erythrocytes will be examined todefine their structure, diversity and function. The components responsible for binding to red cells and theirrole in red blood cell invasion will be clarified. Their specific interactions with molecules of the erythrocytemembrane will be defined, and their pontential to exacerbate anemia examined in field-based studies. Theproperties of parasite lines in which specific genes, coding for components of one of these molecularcomplexes, have been deleted will be studied. The phenotype of these modified parasites may beexpressed as a change of host cell specificity, or different growth rate, or in an alteration of the parasitehostbalance. It is proposed that these genetically manipulated parasites can disturb the mechanisms thatmaintain the red cell equilibrium, leading to dysfunctional control of red cell numbers and consequentanemia. It will be important to establish whether molecules that are potential malaria vaccine candidates arealso the targets of immune mechanisms that promote anemia.
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