The overarching goal of this application is to identify novel mechanisms by which enteroviruses infect the human intestinal epithelium. The events associated with enterovirus infections of the human intestinal epithelium remain largely unknown, largely due to the lack of suitable in vivo models that recapitulate the enteral route of infection in an immunocompetent setting and the inability of standard cultured cells to recapitulate the multicellular nature of the GI epithelium. Using two parallel three-dimensional (3-D) cell models of the human intestinal epithelium recently developed in our laboratory, including a primary stem cell-based model, we have identified several unique mechanisms used by enteroviruses to infect the GI epithelium. The studies proposed in this application will provide important insights into (1) the role of non-lytic release in the enterovirus life cycle in the human intestinal epithelium, (2) the impact of enterovirus infections on intestinal epithelial structure and function, and (3) the role of epithelial host interferon signaling in the control of enteroviral infections. These goals are premised on the central hypothesis that intestinal cell-associated pathways directly impact enterovirus pathogenesis in the human GI tract. Our proposal pioneers research into a variety of aspects of the molecular mechanisms of enterovirus-GI cell interactions. Notably, our research will also illuminate virus specific-pathogenic pathways, which may explain why some enteroviruses are relatively well-tolerated, and others cause severe disease. Given our extensive expertise in enterovirus research, specifically studies related to the GI tract, we are uniquely positioned to perform these studies, which will provide new paradigms for our understanding of enterovirus infections of the GI epithelium.

Public Health Relevance

Enteroviruses are amongst the most common human infections worldwide. These viruses are primarily transmitted via the fecal-oral route, where they target the human gastrointestinal epithelium very early in their infectious life cycles. We propose studies to interrogate the mechanisms by which enteroviruses infect the human GI epithelium utilizing human and mouse models. These studies will provide fundamental insights into the mechanisms by which enteroviruses breach the GI barrier.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI081759-10A1
Application #
10070953
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Park, Eun-Chung
Project Start
2009-07-01
Project End
2025-05-31
Budget Start
2020-06-15
Budget End
2021-05-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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