A genetically attenuated Cryptosporidium strain generates a protective IFN-gamma-independent memory response 4412

Abstract Description The parasite Cryptosporidium is an important enteric pathogen of livestock and a leading cause of diarrhea and death in immunocompromised people and malnourished children. One strategy to reduce the public health impact of Cryptosporidium would be the development of a vaccine to mitigate clinical disease and reduce transmission. The ability to develop a rational strategy for vaccination requires an understanding of the parasite’s genetic program over the course of its life cycle and the immune mechanisms that mediate resistance to this organism. The Cryptosporidium protein HAP2 is expressed in the male gamete and mediates fertilization of the female gamete, a necessary step for parasite replication and production of new oocysts, which propagate the infection. Utilizing an inducible Cre recombinase, we have developed a HAP2 knockout strain of Cryptosporidium that is only able to undergo asexual replication, leading to a truncated infection with low parasite burden. This attenuated infection induces a memory immune response in mice as evidenced by protection from rechallenge at a memory timepoint. While IFN-? produced by T cells is necessary for control of primary Cryptosporidium infection, the protection induced by the HAP2 knockout parasite is still present in IFN-?-/- mice. Through CD4 depletion studies, we show that the T cell response is required for protection, indicating that a T-cell-dependent, IFN-?-independent mechanism of protection is at play at a memory timepoint. Funding Sources Supported by NIH T32-AI007632; R01AI148249-05 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)