Cryptosporidium sp. (Cp) are enteric protozoan parasites that cause significant morbidity and mortality particularly in immunocompromised individuals for whom there is no effective therapy. Our understanding of the immune response to the parasite, particularly with respect to the earliest events by which the parasite is recognized by the host, is incomplete. The overall goal of this project is to understand the mechanism by which the host mucosal immune system initially recognizes and is activated to control Cp. Our preliminary studies have demonstrated the rapid activation of intestinal intraepithelial lymphocytes in response to Cp infection. Our hypothesis is that mucosal lymphocytes of the intestine are necessary for the resistance to and control of Cp in mice through an innate IFNy dependent mechanism.
The specific aims are to: 1) directly demonstrate that mucosal lymphocytes of the intestine are a source of IFNy in mice acutely infected with Cp and 2) that these cells are necessary for innate resistance and control of infection and to determine if the activation of these cells occurs through an antigen independent mechanism. In the first specific aim we will use a transgenic IFNy reporter mouse to demonstrate the early cellular sources of IFNy. In the second aim we will perform adoptive transfer of these cells into IFNy -/- mice prior to challenge with Cp to show that these cells are protective and we will determine if this immune response is antigen independent. This will be accomplished by assessing the resistance of susceptible IFNy -/- mice to Cp infection after the adoptive transfer of CDS T cells specific for ovalbumin (OT-I mice). In summary, this application will focus on the role of mucosal lymphocytes in the primary IFNy dependent immune response in mice to Cp. Better understanding of this innate immune response to Cp, may ultimately lead to the discovery of either pathogen-derived molecules with potent adjuvant properties or host-derived pathogen recognition molecules that could be used in the development of vaccines to enhance the immunity of animals and humans. ? ? ?
