Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6196; pp. 573 - 577
• Main Authors: Reese, T. A., Wakeman, B. S., Choi, H. S., Hufford, M. M., Huang, S. C., Zhang, X., Buck, M. D., Jezewski, A., Kambal, A., Liu, C. Y., Goel, G., Murray, P. J., Xavier, R. J., Kaplan, M. H., Renne, R., Speck, S. H., Artyomov, M. N., Pearce, E. J., Virgin, H. W.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01-08-2014
• Subjects: Animals; Containment; Cytokines; Flavours; Gammaherpesvirinae - genetics; Gammaherpesvirinae - physiology; Gene expression; Gene Expression Regulation, Viral; Genes; Helminthiasis; Herpesvirus 8, Human - genetics; Herpesvirus 8, Human - physiology; Humans; Immune systems; Infections; Interferon-gamma - immunology; Interferon-gamma - pharmacology; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Nematospiroides dubius - immunology; Ovum - immunology; Parasite hosts; Parasites; Pathogens; Promoter Regions, Genetic; Schistosoma mansoni - immunology; Schistosomiasis mansoni - immunology; STAT6 Transcription Factor - metabolism; Strongylida Infections - immunology; Virus Activation - drug effects; Virus Activation - genetics; Virus Activation - physiology; Virus Latency - physiology; Virus Replication - physiology; Viruses; Worms
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1254517

Mammals are coinfected by multiple pathogens that interact through unknown mechanisms. We found that helminth infection, characterized by the induction of the cytokine interleukin-4 (IL-4) and the activation of the transcription factor Stat6, reactivated murine γ-herpesvirus infection in vivo. IL-4 promoted viral replication and blocked the antiviral effects of interferon-γ (IFNγ) by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. IL-4 also reactivated human Kaposi's sarcoma–associated herpesvirus from latency in cultured cells. Exogenous IL-4 plus blockade of IFNγ reactivated latent murine γ-herpesvirus infection in vivo, suggesting a "two-signal" model for viral reactivation. Thus, chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status.