Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis

Qun Lu, Christine C. Yokoyama, Jesse W. Williams, Megan T. Baldridge, Xiaohua Jin, Brittany Desrochers, Traci Bricker, Craig B. Wilen, Juhi Bagaitkar, Ekaterina Loginicheva, Alexey Sergushichev, Darren Kreamalmeyer, Brian C. Keller, Yan Zhao, Amal Kambal, Douglas R. Green, Jennifer Martinez, Mary C. Dinauer, Michael J. Holtzman, Erika C. CrouchWandy Beatty, Adrianus C.M. Boon, Hong Zhang, Gwendalyn J. Randolph, Maxim N. Artyomov, Skip Virgin

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.

Original languageEnglish
Pages (from-to)102-113
Number of pages12
JournalCell Host and Microbe
Volume19
Issue number1
DOIs
StatePublished - Jan 13 2016

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    Lu, Q., Yokoyama, C. C., Williams, J. W., Baldridge, M. T., Jin, X., Desrochers, B., Bricker, T., Wilen, C. B., Bagaitkar, J., Loginicheva, E., Sergushichev, A., Kreamalmeyer, D., Keller, B. C., Zhao, Y., Kambal, A., Green, D. R., Martinez, J., Dinauer, M. C., Holtzman, M. J., ... Virgin, S. (2016). Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Cell Host and Microbe, 19(1), 102-113. https://doi.org/10.1016/j.chom.2015.12.011