Malaria kills approximately one million children each year. However, immunity to malaria severe enough to require hospital admission appears to develop quickly - after only one or two infections, such that the risk of severe disease drops significantly following infancy. The development of this protective natural immunity to malaria correlates with the production of antibodies to malaria parasite antigens that are expressed on the surface of infected erythrocytes. Each malaria parasite possesses a large number of distinct genes encoding these potential parasite surface antigens. Work at our field site in Mali suggests that parasites express a "stealth" subgroup of these antigens more commonly in cerebral malaria - the deadliest form of severe malaria - than in milder forms of malaria. How important is an individual's development of antibodies to parasite surface antigens, particularly this "stealth" subgroup, in the acquisition of immunity to cerebral malaria? This project will measure the association between the risk of cerebral malaria and the presence of antibodies to these parasite surface antigens, with a particular focus on the "stealth" subgroup. We have completed several studies that compare children with cerebral malaria to children who have milder forms of malaria or who are healthy. We will take archived sera from these studies to see how well antibodies bind peptide sequences of surface antigens expressed by malaria parasites. These peptide sequences will come from both surface antigens previously isolated in these studies and, in the second part of our project, a new study of children with cerebral malaria. Multiple peptide sequences will be encoded onto microarray chips, which will then be washed with sera to allow us to study antibody interactions with all of these parasite peptide sequences at once. We predict that sera from young children will not recognize many parasite surface antigen peptide sequences. We also expect that infected children with mild or no malaria symptoms harbor malaria parasites that are recognized by their antibodies, limiting the extent of disease. In contrast, sera from children with cerebral malaria will not recognize peptide sequences of parasite surface antigens as well, particularly not the "stealth" surface antigens associated with cerebral malaria. If this is indeed the case, such "stealth" surface antigens may comprise a potential target for a malaria vaccine to protect against cerebral malaria.
The reason why malaria is as a severe disease in some children is not fully understood. This project seeks to advance our understanding of the mechanisms underlying natural acquired protective immunity to cerebral malaria in the field. This information will be used to better develop therapeutic and preventive approaches that could protect against cerebral malaria.