With the long-term goal of better understanding the role of cholangiocytes (epithelial cells that line bile ducts) in health and disease, the current proposal focuses on the interactions between biliary epithelia and Cryptosporidium parvum (C. parvum), an emerging pathogen important in the development of AIDS-cholangiopathy. Using an in vitro model of biliary cryptosporidiosis established by the authors, they have found that C. parvum activates the NF-kB system in directly infected cholangiocytes; discovered that C. parvum induces apoptosis only in bystander uninfected cholangiocytes via a Fas/FasL dependent mechanism; and demonstrated that C. parvum induces FasL expression and stimulates membrane FasL cleavage in directly infected cholangiocytes. They have also found that while HIV- 1 can not infect cholangiocytes, recombinant biologically active HIV- 1 TAT protein enhances both Fas-mediated and C. parvum-associated apoptosis in cholangiocytes. Based on these preliminary data, the authors propose the novel central hypothesis that C. parvum induces biliary tract disease in patients with AIDS by two interdependent and complementary mechanisms: (i) C. parvum inhibits apoptosis in infected cholangiocytes by activation of the NF-kB survival pathway allowing the organism to parasitize the infected cell to propagate; (ii) C. parvum promotes apoptosis in uninfected cholangiocytes via activation of the Fas/FasL pro-apoptotic pathway and the synergistic effects of HIV-dependent soluble factors such as TAT. They will employ complementary biochemical, molecular and morphologic approaches to address three specific aims: (1) C. parvum activates the NFkB system via direct parasite/host cell membrane interactions and triggers cell survival signals allowing for microbial propagation; (2) C. parvum activates nuclear transcription factors to induce FasL expression in directly infected cholangiocytes and stimulates membrane FasL cleavage; and (3) upregulation of FasL expression and increase of membrane FasL cleavage in C. parvum infected cholangiocytes, synergistically with HIV-1 TAT protein, causes apoptosis in bystander uninfected cells via a Fas/FasL dependent mechanism. Results of these experiments will clarify the molecular mechanisms by which C. parvum is cytopathic for biliary epithelial cells. Innovative aspects of the program include novel methodologies and concepts regarding C. parvum-cholangiocyte interaction. The information generated could provide a theoretical framework for development of novel therapeutic strategies for C. parvum induced AIDS-cholangiopathy.
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