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Gamma interferon controls mouse polyomavirus infection in vivo.

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-?), and Fas did not contribute to control of infection or virus-induced tumors. Gamma interferon (IFN-?) 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-? is an important component of the host defense against MPyV infection and tumorigenesis. In immortalized and primary cells, IFN-? reduces expression of MPyV proteins and impairs viral replication. Mice deficient for the IFN-? receptor (IFN-?R(-/-)) 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-?R(-/-) donor kidneys harbor higher MPyV levels than donor kidneys from wild-type mice. Finally, administration of IFN-? 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-? is an antiviral effector molecule for MPyV infection.

SUBMITTER: Wilson JJ

PROVIDER: S-EPMC3196421 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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Gamma interferon controls mouse polyomavirus infection in vivo.

Wilson Jarad J JJ Lin Eugene E Pack Christopher D CD Frost Elizabeth L EL Hadley Annette A Swimm Alyson I AI Wang Jun J Dong Ying Y Breeden Cynthia P CP Kalman Daniel D Newell Kenneth A KA Lukacher Aron E AE

Journal of virology 20110720 19

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 recent ...[more]

PMID: 21775464

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Project description:Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.

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Gamma interferon controls mouse polyomavirus infection in vivo.

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Gamma interferon controls mouse polyomavirus infection in vivo.

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