Abstract Malaria is a significant problem in endemic areas with approximately 3 billion people at risk and over 200 million clinical cases resulting in between 0.4 and 0.5 million deaths. However, the majority of the population in malaria endemic areas (>60%) is asymptomatic (without overt symptoms), even in high transmission areas. Although identified by circulating Plasmodium-infected red blood cells (iRBCs) in the circulation, the term asymptomatic malaria is a misnomer with individuals experiencing mild anemia and vascular activation, susceptible to co-morbidities such as non-typhoidal Salmonella infections, and acting as a reservoir for infection. Assumed to be controlled by adaptive immunity that builds over several years, this is unlikely to be the case in young children under the age of 2 who have asymptomatic malaria. The long-term goal of this project is to define the genetic and immunological mechanisms that confer asymptomatic malaria in young children before the onset of robust adaptive immunity. Our overarching hypothesis is that genetic variation leading to differential innate immune responses is responsible for controlling asymptomatic malaria. The immunological and genetic underpinnings governing asymptomatic malaria is unknown - there is no genetically intact rodent model to dissect the contributions of allelic variation and individual immunological components. Our working hypothesis is that the collaborative cross (CC) mouse lines, upon infection with Plasmodium yoelii XNL, model human genetic variation to allow identification of QTL associated with the development of mild anemia, a trait associated with asymptomatic malaria in humans. Our preliminary data using specific pathogen free (SPF) wild-caught genetically variable Mus musculus domesticus show a wide variation in anemia and innate immune responsiveness after Plasmodium infection demonstrating that genetic variation in mice could be harnessed to identify the immunological mechanisms associated with asymptomatic malaria. Guided by this preliminary data, the work proposed will be undertaken under a single specific aim: Phenotype 38 CC mouse lines to identify QTLs that govern the level of anemia and innate immune responsiveness to Plasmodium infection. Three sub-aims will 1) determine which CC mouse lines develop asymptomatic malaria 2) begin to map QTLs and identify gene candidates that are associated with development of asymptomatic malaria in mice 3) test the hypothesis that asymptomatic malaria is associated with a robust innate immune response. Once completed, the proposed work is expected to identify key QTLs underlying malarial anemia in mice and discover gene candidates and genetic networks associated with asymptomatic malaria. The proposed research is significant because by identifying the lines that display limited anemia upon P. yoelii XNL infection we will now provide, for the first time, a genetically intact rodent model which can be used to understand how asym...