PATHOPHYSIOLOGY OF BILIARY CRYPTOSPORIDIOSIS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Applicant's Abstract): 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.
StatusFinished
Effective start/end date4/1/006/30/18

ASJC

  • Medicine(all)