Gamma Interferon Controls Mouse Polyomavirus Infection In Vivo▿†

• Type of Material: Article
• Authors: Jarad J. Wilson, Department of Pathology; Eugene Lin, Department of Pathology; Christopher D. Pack, Department of Pathology; Elizabeth L. Frost, Department of Pathology; Annette Hadley, Department of Pathology; Alyson Swimm, Department of Pathology; Jun Wang, Emory University; Ying Dong, Emory University; Cynthia Breeden, Emory University; Daniel Kalman, Emory University; Kenneth Newell, Emory University; Aron E Lukacher, Emory University
• Language: English
• Date: 2011-10
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2011, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128%2FJVI.00761-11
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 85
• Issue: 19
• Start Page: 10126
• End Page: 10134
• Grant/Funding Information: This work was supported by NIH grants RO1 CA71971 (A.E.L.), RO1 AI078426 (K.A.N.), and R01 AI056067 (D.K.).
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Virology

Abstract

Human polyomaviruses are associated with substantial morbidity in immunocompromised patients, including those with HIV/AIDS, recipients of bone marrow and kidney transplants, and individuals receiving immunomodulatory agents for autoimmune and inflammatory diseases. No effective antipolyomavirus agents are currently available, and no host determinants have been identified to predict susceptibility to polyomavirus-associated diseases. Using the mouse polyomavirus (MPyV) infection model, we recently demonstrated that perforin-granzyme exocytosis, tumor necrosis factor alpha (TNF-α), and Fas did not contribute to control of infection or virus-induced tumors. Gamma interferon (IFN-γ) was recently shown to inhibit replication by human BK polyomavirus in primary cultures of renal tubular epithelial cells. In this study, we provide evidence that IFN-γ is an important component of the host defense against MPyV infection and tumorigenesis. In immortalized and primary cells, IFN-γ reduces expression of MPyV proteins and impairs viral replication. Mice deficient for the IFN-γ receptor (IFN-γR−/−) maintain higher viral loads during MPyV infection and are susceptible to MPyV-induced tumors; this increased viral load is not associated with a defective MPyV-specific CD8+ T cell response. Using an acute MPyV infection kidney transplant model, we further show that IFN-γR−/− donor kidneys harbor higher MPyV levels than donor kidneys from wild-type mice. Finally, administration of IFN-γ to persistently infected mice significantly reduces MPyV levels in multiple organs, including the kidney, a major reservoir for persistent mouse and human polyomavirus infections. These findings demonstrate that IFN-γ is an antiviral effector molecule for MPyV infection.