Malaria remains one of the most important infectious diseases in the world today. In 2013 the WHO estimated that 195 million individuals were infected with malaria. Annually, malaria causes 0.5-1.2 million deaths, mostly children. To date, although promising, the best malaria vaccine trials have demonstrated limited efficacy, and while combination therapy and insecticide-treated bed nets have clearly reduced the global burden of malaria, much more needs to be done. The pathogenesis of malaria is intimately linked to the innate immune response which: 1) limits parasite reproduction, 2) is required for the proper processing of antigen in order to achieve acquired immunity and, 3) can be the cause of severe acidosis, life-threatening anemia and cerebral disease that causes death in patients. This latter aspect of the innate immune response represents a real threat to human patients. Malaria parasites elicit inflammatory responses by engaging germ-line encoded innate immune receptors expressed on host leukocytes and tissue cells. Recently we have found that malaria also elicits a type I interferon (IFN) response in patient blood leukocytes. Two parasite products, DNA and hemozoin, disproportionately affect the innate immune response. Hemozoin is very important both because it helps traffic parasite DNA through the host phagolysosomal compartment (where TLR9 is engaged), and then into the cytosol because of its effect on phagolysosomal membrane stability. Furthermore, plasmodial DNA is a potent trigger for IFN production. We hypothesize that malarial infection triggers the cytosolic DNA sensor cyclic-GMP-AMP-synthase (cGAS) and induces production of 2'3'-cGAMP, a second messenger for STimulator of Interferon Genes (STING), leading to type I IFN production. Type I IFNs induce the expression of hundreds of IFN-responsive genes and the strong IFN gene signature in the blood of malaria patients may contribute to the pathogenesis during malarial infection by reprogramming the innate immune effector function of phagocytes and other innate immune cells. Our proposed studies will better define the mechanisms by which malaria drives IFN by determining if cGAS is involved in human disease, and may lead to novel therapeutic strategies.