Cryptosporidium is a ubiquitous pathogen that infects the gastrointestinal epithelium in humans. This parasite is of great medical importance as infections in immunocompromised humans, including AIDS, cancer, and transplant patients, often lead to life-threatening illness. Cryptosporidium is also a common cause of diarrhea in young children in developing countries. There is currently no fully effective therapy available for the infection. Current understanding of the parasite biology and the molecular mechanisms of parasite-host interactions is limited. In our preliminary study, we made a novel observation on the delivery of Cryptosporidium non-coding RNAs (ncRNAs) into the nuclei of infected host cells. Our results also show that cryptosporidial infection suppresses transcription of a panel of genes that code effector proteins key to intestinal epithelial cell differentiation and metabolism. Importantly, transsuppression of this gene panel is associated with enrichment of suppressive epigenetic markers (e.g., H3K9me3) to their gene loci with the involvement of nuclear presence of parasite ncRNAs. Therefore, we will test the hypothesis that cryptosporidial infection induces epigenetic histone methylations in host cells through nuclear delivery of specific parasite ncRNAs, resulting in transcriptional suppression of genes with pathological effects in the host. Using genetic approaches and cutting-edge technologies, we will determine the mechanisms of nuclear delivery of parasite ncRNAs in infected host cells (Aim 1), elucidate how infection induces enrichment of suppressive H3K9 methylation, resulting in transrepression of genes in infected epithelial cells (Aim 2), and determine the role of parasite ncRNA nuclear delivery in the pathogenesis of cryptosporidiosis by assessing its impact on chromatin enrichment of histone methylations in host cells (Aim 3). The results of this study will reveal valuable information abou parasite-host interactions and make possible future investigations aimed at blocking specific transcriptional events as a novel treatment for the infection.

Public Health Relevance

Cryptosporidial infection remains significant in AIDS patients and young children. The proposed research will test how infection induces epigenetic alterations resulting in dysfunction of intestinal epithelium. The outcome of the proposed studies will reveal new mechanisms by which cryptosporidial infection causes disease in AIDS patients and young children, and lead to the development of new therapeutic strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Wali, Tonu M
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Creighton University
Schools of Medicine
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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; 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. (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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