The Cryptosporidium signaling kinase CDPK5 plays an important role in male gametogenesis and parasite virulence

The protozoan parasite Cryptosporidium is a leading cause of diarrhea associated mortality in young children. The parasite’s lifecycle involves a highly coordinated and timely progression from asexual proliferative to sexual stages leading to formation of the transmissible oocyst. Underlying molecular signaling mechanisms orchestrating sexual development are not known. Here, we describe the function of a signaling kinase in Cryptosporidium male gametogenesis. We reveal the expression of Cryptosporidium parvum calcium-dependent protein kinase 5 (CDPK5) during male gamete development, and its important role in egress of mature gametes. Genetic ablation of this kinase results in viable parasites, indicating that this gene is dispensable for parasite survival. Interestingly, cdpk5 deletion significantly decreases parasite virulence and impacts oocyst shedding in immunocompromised mice. Using phosphoproteomics, we identify possible substrates of this kinase. Collectively, these findings illuminate parasite cell biology by revealing an important mechanism controlling male gamete production and identifies a potential target to reduce within-host reinfection as well as block disease transmission.