Immunopathogenesis of Cryptosporidiosis

Both T- and B-cell mediated immunity are believed to play a role in the eradication of and protection from cryptosporidial infections but the mechanisms by which specific components of human host defense mediate successful immunity are unknown. Although many cryptosporidial proteins have been identified, neither their function nor their significance is known. The interaction of Cryptosporidium with its target host cell, the intestinal epithelial cell, and the role of parasite proteins in this interaction has also been little studied. In the proposed studies we will bring the experience and biological samples obtained in over ten years of clinical trials work to the bench in order to begin to unravel the mechanisms by which Cryptosporidium triggers an immune response by virtue of its interaction with the intestinal epithealial cell. In our preliminary analysis of serial serum samples from AIDS patients with chronic cryptosporidiosis, we found that complete clinical and parasitologic resolution of infection coincides with a brisk humoral immune response, and specifically with generation of immunoglobulin directed against a 33 kD cryptosporidial protein (p-33). This project focuses on characterization of p-33 and investigation of its potential role as a virulence factor. Furthermore, the proposed studies provide a novel approach to the study of immune function in cryptosporidial infection because they will focus on the potential role of p-33 as a T-cell antigen. Our specific aims are to: (1) characterize the 33 kD cryptosporidial protein, and (2) explore the potential role of p- 33 as a T-cell dependent antigen. As there are no models in place for work related to Aim 2, we have adopted an innovative approach for developing useful models for the study of intestinal immunity against Cryptosporidium.