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Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier

Nature Immunology volume 5, pages 1266–1274 (2004)Cite this article

Abstract

Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal–regulated kinase (Erk) signaling, which was integrated to interferon regulatory factor 3 activation and type I interferon induction. We further show that Erk inactivation or disruption of interferon signaling mediated by the transcription factor STAT1 broke the cellular blockade to myxoma virus multiplication. Moreover, STAT1 deficiency rendered mice highly susceptible to lethal myxoma virus infection. Thus, the Erk–interferon–STAT1 signaling cascade elicited by myxoma virus in nonpermissive primary mouse embryo fibroblasts mediates an innate cellular barrier to poxvirus infection.

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Figure 1: Erk1/2 signaling restricts myxoma virus replication.
Figure 2: Type I interferon induction mediates the cellular restriction of myxoma virus replication.
Figure 3: Erk1/2 signaling is required for optimal induction of type I interferon.
Figure 4: STAT1 activation by type I interferon does not require Erk1/2 participation.
Figure 5: Erk1/2 signaling is linked to IRF3 activation.
Figure 6: Myxoma virus infection elicits PKR-independent, STAT1-mediated eIF2α phosphorylation.
Figure 7: PKR, RNase L and Mx1 are not involved in Erk1/2-induced cellular restriction of myxoma virus multiplication.
Figure 8: STAT1 deficiency renders mice highly susceptible to lethal myxoma virus infection.

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Acknowledgements

We thank R. Schreiber, G. Stark, H. Nguyen, A. Koromilas, D. Frank, R. Silverman, B. Williams, J. Ihle, M. Aguet, K. Mossman and D. Barber for their advice and reagents, which helped in the development of this project, and D. Hall for help with the manuscript. Supported by the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Robarts Research Institute, and Department of Microbiology and Immunology, The University of Western Ontario, London, N6G 2V4, Ontario, Canada

    Fuan Wang, Yiyue Ma, John W Barrett, Xiujuan Gao & Grant McFadden

  2. Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Joy Loh, Erik Barton & Herbert W Virgin IV

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Correspondence to Grant McFadden.

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Wang, F., Ma, Y., Barrett, J. et al. Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat Immunol 5, 1266–1274 (2004). https://doi.org/10.1038/ni1132

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