Cryptosporidium uses CSpV1 to activate host type I interferon and attenuate antiparasitic defenses

Abstract

Cryptosporidium infects gastrointestinal epithelium and is a leading cause of infectious diarrhea and diarrheal-related death in children worldwide. There are no vaccines and no fully effective therapy available for the infection. Type II and III interferon (IFN) responses are important determinants of susceptibility to infection but the role for type I IFN response remains obscure. Cryptosporidium parvum virus 1 (CSpV1) is a double-stranded RNA (dsRNA) virus harbored by Cryptosporidium spp. Here we show that intestinal epithelial conditional Ifnar1−/− mice (deficient in type I IFN receptor) are resistant to C. parvum infection. CSpV1-dsRNAs are delivered into host cells and trigger type I IFN response in infected cells. Whereas C. parvum infection attenuates epithelial response to IFN-γ, loss of type I IFN signaling or inhibition of CSpV1-dsRNA delivery can restore IFN-γ-mediated protective response. 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 epithelial antiparasitic response.

A Parasite Odyssey: An RNA virus concealed inToxoplasma gondii

“…found that induction of type I IFN in the COUGAR strain is dependent upon the RNA-sensor RIG-I, and the signal cascade proceeds through MyD88/TRIF and ultimately IRF3, an inducer of type I IFN (Melo et al, 2013). IRF3 phosphorylation and IFN-induction are also observed in other PPV infections, albeit with a double-stranded RNA ligand (Ives et al, 2011; Fichorova et al, 2012; Eren et al, 2016; Deng et al, 2023). Not knowing of the existence of Ao within their experiment, the authors ascribe COUGAR/RUB hypervirulence to parasite genomic DNA/RNA, potentially associated with the enhanced killing observed in human foreskin fibroblasts, leading to release of greater quantities of Toxoplasma nucleic acids (Melo et al, 2013).…”

“…(Ives et al, 2011; Eren et al, 2016), GLV1 in Giardia lamblia (Pu et al, 2021) and CSpV1 in Cryptosporidia sp. (Deng et al, 2023). Unlike Ao, previously-characterised PPVs are double-stranded RNA viruses, and a narnavirus contributing to disease in vertebrates has not yet been characterized.…”

“…For example, the dsRNA virus Cryptosporidium parvum virus 1 (CSpV1) which infects Cryptosporidium parvum , activates a type I IFN inflammatory cascade in mouse and cell culture models. Interestingly, this response undermines host defences against C. parvum , as evidenced by the enhanced antiparasitic immunity observed in mice lacking type I IFN receptor in their intestinal epithelia (Deng et al, 2023). While the underlying mechanism for the inflammation remains elusive, PPV presence appears to be necessary for parasite pathogenicity, potentially by diverting the host’s innate immune system towards the activation of antiviral immunity and away from antiparasitic immunity.…”

Cryptosporidiuminfection of human small intestinal epithelial cells induces type III interferon and impairs infectivity of Rotavirus

“…Hence, a difference in CSpV1 load between the two species might explain the observed difference in induction of type III IFN, as well as the difference in CCL5 expression, which is regulated by the IRF3 pathway downstream of TLR3 (42). Furthermore, CSpV1 has recently been involved in cryptosporidiosis pathophysiology by inducing the type I IFN pathway, inhibiting in turn the IFN-γ pathway, providing a form of protection against the immune response to the parasite (43). It is worth noting that in this study, type I IFN activation by CSpV1 was not dependent of TLR3, but instead on the Pkr and Rig-I/Mavs/Sting signaling pathways (43).…”

“…Furthermore, CSpV1 has recently been involved in cryptosporidiosis pathophysiology by inducing the type I IFN pathway, inhibiting in turn the IFN-γ pathway, providing a form of protection against the immune response to the parasite (43). It is worth noting that in this study, type I IFN activation by CSpV1 was not dependent of TLR3, but instead on the Pkr and Rig-I/Mavs/Sting signaling pathways (43). In any case, further exploration of the role of CSpV1 in cryptosporidiosis pathophysiology, using more direct methods, is warranted.…”