Molecular basis of intestinal cryptosporidiosis

Summary
Cryptosporidium remains a significant AIDS-related opportunistic infection among people with late HIV
diagnosis or without access to HAART. This parasite infects the gastrointestinal epithelium in humans;
infection is also a common cause of diarrhea in young children in developing countries. There is currently no
fully effective therapy available for the infection. Cryptosporidium has been referred as a “minimally invasive”
mucosal pathogen, and epithelial antimicrobial defense is key to mucosal innate anti-Cryptosporidium
immunity. Whereas it is well appreciated that Type II interferon-gamma (IFN-γ) is required for preventing
development of intestinal cryptosporidiosis, recent advances have revealed a significant Type I IFN response
(e.g., induction of IFN-alpha and IFN-beta) in host epithelium following C. parvum infection. The molecular
mechanisms underlying Type I IFN response and its potential role in the pathogenesis of cryptosporidiosis are
unclear.
Cryptosporidium parvum virus 1
(CSpV1) is a member of the family Partitiviridae, genus Cryspovirus
that infects C. parvum and other Cryptosporidium spp. Our recent studies demonstrate that host delivery of
CSpV1-RNAs at the host-parasite interface can trigger a Type I IFN response in host cells. C. parvum infection
attenuates intestinal epithelial cell response to IFN-γ stimulation (i.e., infected cells are less susceptible to
activation by IFN-γ). Surprisingly, knockout Type I IFN signaling in intestinal epithelial cells or inhibition of
CSpV1-RNA delivery can restore cellular response to IFN-γ stimulation and promotes resistance to C. parvum
infection, suggesting a negative impact of Type I IFN signaling on epithelial anti-Cryptosporidium defense.
Based on these observations, we hypothesize that cryptosporidial infection triggers Type I IFN response in the
intestinal epithelium and attenuates IFN-γ-mediated epithelial antimicrobial defense through delivery of CSpV1-
RNAs. We will use in vitro, ex vivo, and in vivo infection models and complementary biochemical, molecular,
and morphologic approaches to elucidate the molecular mechanisms by which Cryptosporidium infection
triggers Type I IFN gene transcription in the intestinal epithelium (Aim 1), determine how Cryptosporidium
infection modulates the JAK/STAT signaling in infected intestinal epithelial cells (Aim 2), and define the impact
of Cryptosporidium-induced JAK/STAT signaling dysregulation on epithelial anti-parasite defense (Aim 3). The
proposal is conceptually innovative as it tests a novel mechanism for symbiotic CSpV1 in the pathogenesis of
cryptosporidiosis and has the potential to inform future development of new therapeutic strategies.

Grant Number: 5R01AI116323-10
NIH Institute/Center: NIH
Principal Investigator: Xian-Ming Chen