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-?) 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-? stimulation (i.e., infected cells are less susceptible to activation by IFN-?). Surprisingly, knockout Type I IFN signaling in intestinal epithelial cells or inhibition of CSpV1-RNA delivery can restore cellular response to IFN-? 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-?-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.

Public Health Relevance

Health Relevance Cryptosporidial infection remains significant in AIDS patients and young children. The proposed research will study the molecular mechanisms by which Cryptosporidium interacts with host epithelial cells and evades host defense, and could potentially be exploited for the development of new therapeutic strategies targeting these mechanisms.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1)
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Pesce, John T
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Creighton University
Schools of Medicine
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Ming, Zhenping; Wang, Yang; Gong, Ai-Yu et al. (2018) Attenuation of Intestinal Epithelial Cell Migration During Cryptosporidium parvum Infection Involves Parasite Cdg7_FLc_1030 RNA-Mediated Induction and Release of Dickkopf-1. J Infect Dis 218:1336-1347
Ming, Zhenping; Gong, Ai-Yu; Wang, Yang et al. (2018) Trans-suppression of defense DEFB1 gene in intestinal epithelial cells following Cryptosporidium parvum infection is associated with host delivery of parasite Cdg7_FLc_1000 RNA. Parasitol Res 117:831-840
Li, Min; Gong, Ai-Yu; Zhang, Xin-Tian et al. (2018) Induction of a Long Noncoding RNA Transcript, NR_045064, Promotes Defense Gene Transcription and Facilitates Intestinal Epithelial Cell Responses against Cryptosporidium Infection. J Immunol 201:3630-3640
Ming, Zhenping; Gong, Ai-Yu; Wang, Yang et al. (2018) Trans-suppression of host CDH3 and LOXL4 genes during Cryptosporidium parvum infection involves nuclear delivery of parasite Cdg7_FLc_1000 RNA. Int J Parasitol 48:423-431
Zhao, Guang-Hui; Gong, Ai-Yu; Wang, Yang et al. (2018) Nuclear delivery of parasite Cdg2_FLc_0220 RNA transcript to epithelial cells during Cryptosporidium parvum infection modulates host gene transcription. Vet Parasitol 251:27-33
Ming, Zhenping; Gong, Ai-Yu; Wang, Yang et al. (2017) Involvement of Cryptosporidium parvum Cdg7_FLc_1000 RNA in the Attenuation of Intestinal Epithelial Cell Migration via Trans-Suppression of Host Cell SMPD3. J Infect Dis 217:122-133
Wang, Yang; Gong, Ai-Yu; Ma, Shibin et al. (2017) Delivery of parasite Cdg7_Flc_0990 RNA transcript into intestinal epithelial cells during Cryptosporidium parvum infection suppresses host cell gene transcription through epigenetic mechanisms. Cell Microbiol 19:
Ma, Shibin; Ming, Zhenping; Gong, Ai-Yu et al. (2017) A long noncoding RNA, lincRNA-Tnfaip3, acts as a coregulator of NF-?B to modulate inflammatory gene transcription in mouse macrophages. FASEB J 31:1215-1225
Ming, Z; Zhou, R; Chen, X-M (2017) Regulation of host epithelial responses to Cryptosporidium infection by microRNAs. Parasite Immunol 39:
Mathy, Nicholas W; Chen, Xian-Ming (2017) Long non-coding RNAs (lncRNAs) and their transcriptional control of inflammatory responses. J Biol Chem 292:12375-12382

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