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

Cell Host & Microbe
Sunmin ParkHerbert W Virgin

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.

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Citations

Jan 15, 2016·Cell Host & Microbe·William Khoury-Hanold, Akiko Iwasaki
Jul 17, 2016·Immunologic Research·David H Dreyfus
Sep 2, 2016·Frontiers in Microbiology·Brandon CieniewiczLaurie T Krug
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Nov 18, 2017·Annual Review of Immunology·Yu Matsuzawa-IshimotoKen Cadwell
Mar 3, 2018·The Journal of Biological Chemistry·Christine C YokoyamaHerbert W Virgin
Mar 10, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Yi Sak KimEun-Kyeong Jo
Oct 10, 2018·Infection and Immunity·Jeremy BechelliRong Fang
Jan 4, 2020·Cell Death and Differentiation·Matthew D KellerKen Cadwell
Sep 6, 2018·Molecular Neurobiology·Catherine H Schein
Aug 28, 2019·Viruses·Hai-Chang YinTian-Fei Yu
Apr 4, 2017·Médecine sciences : M/S·Isabelle VergneMartine Biard-Piechaczyk
Apr 14, 2018·Science·Craig B WilenHerbert W Virgin
Dec 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Dale R BalceHerbert W Virgin
Sep 30, 2021·Annual Review of Virology·Yiping WangLaurie T Krug

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Methods Mentioned

BETA
lipidation
PCR
PECs
RNA-seq
flow cytometry
ELISA
transgenic

Software Mentioned

GraphPad Prism

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