Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation

Sunmin Park, Michael D. Buck, Chandni Desai, Xin Zhang, Ekaterina Loginicheva, Jennifer Martinez, Michael L. Freeman, Tatsuya Saitoh, Shizuo Akira, Jun Lin Guan, You Wen He, Marcia A. Blackman, Scott A. Handley, Beth Levine, Douglas R. Green, Tiffany A. Reese, Maxim N. Artyomov, Herbert W. Virgin

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Murine gammaherpesvirus 68 (MHV68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (IFN-γ). Using a lysozyme-M-cre (LysMcre) expression system, we show that deletion of autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16l1, Atg7, Atg3, and Atg5, in the myeloid compartment, inhibited MHV68 reactivation in macrophages. Atg5 deficiency did not alter reactivation from B cells, and effects on reactivation from macrophages were not explained by alterations in productive viral replication or the establishment of latency. Rather, chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-γ, and an IFN-γ-induced transcriptional signature in macrophages from Atg gene-deficient mice. The Atg5-related reactivation defect was partially reversed by neutralization of IFN-γ. Thus Atg genes in myeloid cells dampen virus-induced systemic inflammation, creating an environment that fosters efficient MHV68 reactivation from latency.

Original languageEnglish
Pages (from-to)91-101
Number of pages11
JournalCell Host and Microbe
Volume19
Issue number1
DOIs
StatePublished - Jan 13 2016

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    Park, S., Buck, M. D., Desai, C., Zhang, X., Loginicheva, E., Martinez, J., Freeman, M. L., Saitoh, T., Akira, S., Guan, J. L., He, Y. W., Blackman, M. A., Handley, S. A., Levine, B., Green, D. R., Reese, T. A., Artyomov, M. N., & Virgin, H. W. (2016). Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation. Cell Host and Microbe, 19(1), 91-101. https://doi.org/10.1016/j.chom.2015.12.010