It is well established that human genetic variation modulates human susceptibility to infection and disease. Using a genome-wide association study, we previously identified PRKCA (the gene encoding protein kinase c alpha, PKCα) as a significant susceptibility locus for cryptosporidiosis infection in the first year of life in Bangladeshi infants (P<5x10-8). Cryptosporidium invasion activated host PKCα in HCT-8 human intestinal epithelial cells and manipulation of PKCα activity modulated parasite invasion of epithelial cells in vitro. Surprisingly, in vivo experiments with PRKCA-/- deletion mice found they were no more susceptible to primary Cryptosporidium infection than their wild type littermates. However, transcriptional profiling identified significantly dysregulated B cell activation pathways in duodenal tissue in the absence of PKCα both during and after Cryptosporidium infection. This observation lead us to hypothesize that PKCα influences B-cell activation and the development of protective adaptive immune responses during Cryptosporidium infection. Indeed, upon Cryptosporidium reinfection PRKCA-/- had decreased shedding, and accelerated parasite clearance relative to wild-type. Correspondingly, B cell populations and anti-Cryptosporidium antibody responses were altered in the absence of PKCα. Our data suggest that variants in host PKCα have the potential to impact human susceptibility to Cryptosporidium both via direct invasion of epithelial cells (in vitro data) and by influencing the development of protective adaptive immunity (in vivo data). We are currently evaluating these two possibilities in a newly enrolled birth cohort of Bangladeshi infants followed prospectively for cryptosporidiosis (both subclinical and acute) for the first 3 years of life.