Pathophysiology of Cryptosporidiosis

Current projects are related to NIH R01 DK57993.

Our lab is interested in the interactions between cholangiocytes and Cryptosporidium parvum, a Biodefense Category B priority protozoon parasite. C. parvum is an enteric pathogen and common cause of gastroenteritis in humans and animals worldwide. In immunocompetent individuals, infection is limited to the intestine and causes acute, self-limited disease.  However, in the immunosuppressed, biliary cryptosporidiosis may cause potentially fatal complications, including bile duct damage.  This work is supported by another R01 (DK 57993), which probes the molecular mechanisms of pathogen recognition and intracellular signaling cascades involved in the cholangiocyte innate immune response. Recent evidence indicates: (i) the cellular expression and regulation of key receptors [Toll-like receptors (TLRs)] and specific intracellular signaling pathways (NF-kB activation) are involved in cholangiocyte C. parvum recognition and defense response; and (ii) endogenous microRNA (miRNA)-mediated post-transcriptional gene regulation is involved in cholangiocyte defense responses to C. parvum infection.  Therefore, cholangiocytes integrate both transcriptional and post-transcriptional gene regulation in the initiation of a defense response to this pathogen.  Thus, we are testing the CENTRAL HYPOTHESIS that C. parvum-cholangiocyte interactions activate host-cell TLR/NF-kB signaling cascades initiating cholangiocyte defense responses including upregulation of both TLRs and anti-microbial peptides (defensins) through both transcriptional and post transcriptional (endogenous miRNA-mediated) gene regulation.  In our three integrated SPECIFIC AIMS, we test the hypotheses that: (i) cholangiocyte TLRs recognize C. parvum and modulate NF-kB activation resulting in upregulation if anti-microbial peptides [human beta-defensins ( HBDs) ] and TLRs through NF-kB mediated transcriptional regulation; (ii) miRNA-mediated post- transcriptional repression of TLR expression normally exists in cholangiocytes, is regulated by TLR/NF-kB signals, and is involved in C. parvum-induced upregulation of TLRs; and (iii) expression of TLRs and HBDs in cholangiocytes are required for eradication of C. parvum infection in the biliary tract in in vitro and in vivo experimental models.