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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116323-04
Application #
9419285
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Wali, Tonu M
Project Start
2015-02-04
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Creighton University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178