# Molecular basis of intestinal cryptosporidiosis

> **NIH NIH R01** · CREIGHTON UNIVERSITY · 2020 · $402,997

## Abstract

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.

## Key facts

- **NIH application ID:** 10019152
- **Project number:** 2R01AI116323-06
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Xian-Ming Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,997
- **Award type:** 2
- **Project period:** 2015-02-04 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019152

## Citation

> US National Institutes of Health, RePORTER application 10019152, Molecular basis of intestinal cryptosporidiosis (2R01AI116323-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10019152. Licensed CC0.

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