This application is intended to support a 4 year mentored patient-oriented research career development award (K23) for Kirsten E. Lyke, MD to become an independent investigator in international health. It will provide Dr. Lyke the support, training and mentoring that will further a career in research and control disease impacting global health. Plasmodium falciparum malaria remains a devastating cause of morbidity and mortality in sub-Saharan Africa. Vaccine development has been impeded by the complexity of the parasitic life cycle, the intra-erythrocytic nature of the blood stage organism, the regional antigenic variability of the parasite and incomplete knowledge of the host immune response to plasmodia. Despite these obstacles, a number of vaccine candidates show promise and await implementation in field-based Phase III trials. Vaccine development depends on reproducing in field studies host immune responses to predetermined malarial antigens observed in Phase I and II studies. Little investigation has been done to analyze factors that may alter this predictable host immune response. Co-infection with multiple parasites is common in malaria endemic areas although little is known about the immune response of concurrent infections. Plasmodium falciparum and Schistosoma haematobium/mansoni are co-endemic parasitic diseases with worldwide distribution. Preliminary evidence from field studies in Bandiagara, Mali suggests that the presence of chronic schistosomiasis infection may ameliorate the pathologic effects of acute falciparurn malaria. Murine models, in contrast, suggest that detrimental immune effects occur resulting in more severe parasitemia, severe anemia and increased severity of disease. The discrepancies remain a source of confusion. The chief objective of this project is to test the hypothesis that co-infected individuals with chronic schistosomiasis (S. haematobium/mansoni) and acute malaria (P. falciparum) have an immunologic interaction that shifts the balance from the expected Th1 cell-mediated immune response towards a helminth-induced humoral-mediated Th2 response. We seek to investigate the immunological interaction of these two infections by assessing the disruption in cytokine balance in co-infected individuals versus falciparum malaria infected hosts to determine if severity of malarial disease and the underlying immune response are different. These studies are expected to provide crucial knowledge that will have direct implications for vaccine development and testing at this and other sites, as and to illuminate the complex interaction of dual parasitic infections that plague so much of the developing world.
