Coxsackievirus B (CVB), a member of the enterovirus family of RNA viruses, is associated with a number of diverse syndromes, including meningitis, pericarditis, febrile illness, diabetes, dilated cardiomyopathy and myocarditis. A key event in CVB pathogenesis is the induction of host cell death. Enteroviruses are lytic viruses and possess no known mechanism for progeny release other than the destruction of the host cell membrane. However, cell death induction must be balanced precisely as activating cell death prematurely, or by alternative pathways, could inhibit replication and/or induce inflammatory signaling. Whereas CVB commonly induces apoptosis in many non-polarized cell types, we have shown that CVB-infected polarized intestinal epithelial cells undergo necrosis, which is required for virus egress. However, the molecular basis for this difference has remained elusive. In this proposal, we will extend our previous studies to provide a mechanistic understanding of the pathways that mediate CVB- induced intestinal cell death and how these pathways might affect CVB pathogenesis and inflammatory signaling. We will (1) define the role of the pro-necrotic serine/threonine nonreceptor kinase receptor-interacting protein 3 (RIP3) in CVB-induced necrotic cell death of the intestinal epithelium, (2) define the mechanisms employed by CVB to attenuate RIP3- mediated signaling, and (3) define the role of necrotic cell death in CVB-induced destruction of the epithelial barrier and inflammatory signaling. These studies provide critical insights into the molecular events that promote necrotic signaling in response to CVB, and possible other RNA virus, infection within the intestinal epithelium. In addition, these studies will identify previously unknown host targets that could be targeted to enhance antiviral defenses and/or limit CVB- induced egress from and inflammation of the gastrointestinal tract.

Public Health Relevance

Coxsackievirus B (CVB) is a significant source of human disease and is commonly associated with myocarditis, dilated cardiomyopathy, and aseptic meningitis. There are currently no effective therapeutics available to combat CVB infections. We have uncovered a novel mechanism by which CVB alters host cell biology that may play a pivotal role in developing strategies for mitigating CVB-induced cell injury and inflammation within the gastrointestinal tract, the primary site of CVB host entry

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI081759-05A1
Application #
8628266
Study Section
Virology - A Study Section (VIRA)
Program Officer
Park, Eun-Chung
Project Start
2009-07-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$193,852
Indirect Cost
$46,286
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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