Malaria continues to cause marked morbidity and mortality worldwide. Infection can result in severe life threatening disease, mild symptoms or an asymptomatic carriage state. Protection from severe disease outcomes naturally occurs in residents high Plasmodium falciparum transmission regions This protection is related to repeated malaria exposures which result in mild to asymptomatic carriage rather than devastating complications which occurs in non-immune individuals. The basis of this clinical observation made decades ago remains poorly characterized. Our group and others have identified a role for type IINF response during malarial infection. Type I INF is known as a powerful immunomodulatory molecule that can promote activation, differentiation or even apoptosis of effector cells such as NK and T lymphocytes ahd favor cross-priming by DCs. Thus our working hypothesis proposes that a stronger type I IFN response in malaria infections is associated with a more protective host innate and adaptive immune responses. We will examine the role of type I INF during mild malaria and whether this response changes during repeated infections in one individual, alters the risk of re-infection and is associated with transmission intensity. This proposal brings Dr. Lauvau's expertise in studying immune responses against microbial pathogens, Dr. Daily's expertise in transcriptional analysis with the Malawi ICEMR program to characterize innate and subsequent adaptive immune responses in children with mild disease in a longitudinal study. This proposal will enhance the Malawi ICEMR goals of understanding the determinants of malarial disease. Host immune responses alter the development of malarial disease and thus this proposal will provide a further characterization of host responses to inform disease models. We will also address how changes in transmission intensity through malaria control interventions in the parent study may alter host response and disease presentation. Finally this proposal will further the training mission of the Malawi ICEMR by training Malawian scientists and building in-country laboratory and scientific capacity in malaria immunology.