Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, a...

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Bibliographic Details
Published in:	Journal of virology Vol. 91; no. 1
Main Authors:	Mboko, Wadzanai P, Rekow, Michaela M, Ledwith, Mitchell P, Lange, Philip T, Schmitz, Kaitlin E, Anderson, Sean, Tarakanova, Vera L
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-01-2017
Subjects:	Animals Antigens, Differentiation, Myelomonocytic - genetics Antigens, Differentiation, Myelomonocytic - immunology Antigens, Nuclear - genetics Antigens, Nuclear - immunology Gammaherpesvirinae Gammaherpesvirinae - growth & development Gammaherpesvirinae - pathogenicity Gene Expression Regulation Herpesviridae Infections - genetics Herpesviridae Infections - immunology Herpesviridae Infections - mortality Herpesviridae Infections - virology Host-Pathogen Interactions Humans Interferon Regulatory Factor-1 - genetics Interferon Regulatory Factor-1 - immunology Interferon Regulatory Factor-3 - genetics Interferon Regulatory Factor-3 - immunology Interferon Regulatory Factor-7 - genetics Interferon Regulatory Factor-7 - immunology Interferon-alpha - genetics Interferon-alpha - immunology Interferon-beta - genetics Interferon-beta - immunology Interferon-gamma - genetics Interferon-gamma - immunology Interferon-Induced Helicase, IFIH1 - genetics Interferon-Induced Helicase, IFIH1 - immunology Lung - immunology Lung - virology Macrophages - immunology Macrophages - virology Mice Mice, Inbred C57BL Mice, Knockout Pathogenesis and Immunity Primary Cell Culture Proteins - genetics Proteins - immunology Receptor, Interferon alpha-beta - genetics Receptor, Interferon alpha-beta - immunology Signal Transduction Spleen - immunology Spleen - virology Survival Analysis viral replication IRF-1 gammaherpesvirus acute infection interferon
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Summary:	Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection. Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Mboko WP, Rekow MM, Ledwith MP, Lange PT, Schmitz KE, Anderson S, Tarakanova VL. 2017. Interferon regulatory factor 1 and type I interferon cooperate to control acute gammaherpesvirus infection. J Virol 91:e01444-16. https://doi.org/10.1128/JVI.01444-16.
ISSN:	0022-538X 1098-5514
DOI:	10.1128/jvi.01444-16