PATHOGENESIS OF INTESTINAL CRYPTOSPORIDIOSIS IN AIDS

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Cryptosporidium parvum is the most common single infectious cause of diarrhea in AIDS patients (AIDS-associated diarrhea). Unfortunately, the infection has failed to respond to a large variety of treatment regimens, with the possible exception of a limited response to spiramycin and a controversial effect of bovine milk antibody in some patients. The basic biology and pathogenic mechanisms involved in the interaction between the parasite and the intestinal epithelium is poorly understood, and the mechanism of the diarrhea itself is unknown, hence it has been impossible to develop rational intervention or prevention strategies. It is unlikely that significant progress can be made without basic studies to understand the mechanisms of pathogenesis of this most important intestinal manifestation of AIDS. In this project we intend to do just this, by examining the surface of oocysts and sporozoites of C. parvum for the presence of antigenic determinants that may allow classification of isolates into subgroups based on antigens and clinical virulence in the host, to identify surface components that may be involved in parasite recognition of the intestinal cell and in the invasion of the enterocyte, to determine the impact of polyclonal or monoclonal antibody to specific surface constituents of the organism on attachment and/or invasion of the enterocyte, to search for sugar specific binding mechanisms in this interaction, to investigate the chemical nature of the cyst wall and to obtain clues to the biochemistry of encystation, and to determine the secretory immune response to the organism. Organisms will be obtained from human AIDS patients with chronic C. parvum infection, amplified by transmission to young calves to supply stocks of oocysts for study, monoclonal and polyclonal antibodies will be developed in mice and rabbits immunized with crude and purified antigens, assays for attachment invasion will be set up or developed for the purpose, and pathogenic properties of the organism will be evaluated using in vivo small animal models and in vitro systems designed to reveal specific characteristics of the relevant cell-cell interactions. The ultimate goal is to determine the immunogens to be used in a vaccine for active or passive immunization.