Cryptosporidium Uses Its Cspv1 Virus to Activate Host Type I IFN Response and Attenuate IFN-Gamma-Mediated Epithelial Anti-Parasitic Defense
Cryptosporidium, an apicomplexan protozoan parasite that infects the gastrointestinal epithelium, is a leading cause of infectious diarrhea and diarrheal-related death in young children worldwide and an opportunistic pathogen in immunocompromised individuals such as HIV/AIDS patients. There is no vaccine nor fully effective drug available to treat Cryptosporidium infection. C. parvum and C. hominis are the most common species that infect humans. Cryptosporidium oocysts are ingested from contaminated water or food and invade the intestinal epithelial cells. After invasion, the parasite keeps an intracellular but extracytoplasmic position inside a parasitophorous vacuole, rendering intestinal epithelial cells the major battleground between parasite and host anti-parasitic defense. Interferon (IFN) family is a group of cytokines that play essential roles in host innate and adaptive immunity against pathogen infections. There are three types of IFNs and all three types of IFN signaling have been observed in intestinal epithelium following Cryptosporidium infection. The activation of type II and III IFN signaling is mediated through toll-like receptors (TLRs). Both type II and type III IFNs are important determinants of susceptibility to infection. However, the induction of the type I IFN response and its role in host anti-parasitic defense remains poorly defined. Cryptosporidium parvum virus 1 (CSpV1) is a double-stranded RNA (dsRNA) virus harbored by C. parvum. This study shows that intestinal epithelial conditional Ifnar1-/-(type I IFN receptor deficient) mice are resistant to C. parvum infection. Moreover, CSpV1-dsRNAs are delivered into infected cells and trigger a type I IFN response. Whereas C. parvum infection can attenuate epithelial response to type II IFN (IFN-γ), a loss of type I IFN signaling, or inhibition of CSpV1-dsRNA delivery can restore an IFN-γ-mediated protective response. The attenuation of the type II IFN response involves the type I IFN signaling dependent induction of Usp18 expression, as depletion of Usp18 in intestinal epithelial cells enhances the cellular response to IFN-γ and restores IFN--mediated defense in infected cells. Thus, our findings demonstrate that type I IFN signaling in intestinal epithelial cells is detrimental to intestinal anti-C. parvum defense and Cryptosporidium uses CSpV1 to activate type I IFN signaling to evade an IFN-γ-mediated epithelial anti-parasitic defense.
Cryptosporidium, Host-Parasite Interaction, Interferon
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