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

T. A. Reese; B. S. Wakeman; H. S. Choi; M. M. Hufford; S. C. Huang; X. Zhang; M. D. Buck; A. Jezewski; A. Kambal; C. Y. Liu; G. Goel; P. J. Murray; R. J. Xavier; M. H. Kaplan; R. Renne; S. H. Speck; M. N. Artyomov; E. J. Pearce; H. W. Virgin

doi:10.1126/science.1254517

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

T. A. Reese, B. S. Wakeman, H. S. Choi, M. M. Hufford, S. C. Huang, X. Zhang, M. D. Buck, A. Jezewski, A. Kambal, C. Y. Liu, G. Goel, P. J. Murray, R. J. Xavier, M. H. Kaplan, R. Renne, S. H. Speck, M. N. Artyomov, E. J. Pearce, H. W. Virgin

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Abstract

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.

Original language	English (US)
Pages (from-to)	573-577
Number of pages	5
Journal	Science
Volume	345
Issue number	6196
DOIs	https://doi.org/10.1126/science.1254517
State	Published - Aug 1 2014

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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. (2014). Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter. Science, 345(6196), 573-577. https://doi.org/10.1126/science.1254517

Reese, TA, Wakeman, BS, Choi, HS, Hufford, MM, Huang, SC, Zhang, X, Buck, MD, Jezewski, A, Kambal, A, Liu, CY, Goel, G, Murray, PJ, Xavier, RJ, Kaplan, MH, Renne, R, Speck, SH, Artyomov, MN, Pearce, EJ & Virgin, HW 2014, 'Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter', Science, vol. 345, no. 6196, pp. 573-577. https://doi.org/10.1126/science.1254517

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abstract = "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.",

author = "Reese, {T. A.} and Wakeman, {B. S.} and Choi, {H. S.} and Hufford, {M. M.} and Huang, {S. C.} and X. Zhang and Buck, {M. D.} and A. Jezewski and A. Kambal and Liu, {C. Y.} and G. Goel and Murray, {P. J.} and Xavier, {R. J.} and Kaplan, {M. H.} and R. Renne and Speck, {S. H.} and Artyomov, {M. N.} and Pearce, {E. J.} and Virgin, {H. W.}",

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AU - Wakeman, B. S.

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AU - Huang, S. C.

AU - Zhang, X.

AU - Buck, M. D.

AU - Jezewski, A.

AU - Kambal, A.

AU - Liu, C. Y.

AU - Goel, G.

AU - Murray, P. J.

AU - Xavier, R. J.

AU - Kaplan, M. H.

AU - Renne, R.

AU - Speck, S. H.

AU - Artyomov, M. N.

AU - Pearce, E. J.

AU - Virgin, H. W.

PY - 2014/8/1

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N2 - 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.

AB - 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.

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

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