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. Crouch; Wandy Beatty; Adrianus C.M. Boon; Hong Zhang; Gwendalyn J. Randolph; Maxim N. Artyomov; Herbert W. Virgin

doi:10.1016/j.chom.2015.12.011

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, Herbert W. Virgin

Physiology

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67 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 language	English (US)
Pages (from-to)	102-113
Number of pages	12
Journal	Cell Host and Microbe
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2015.12.011
State	Published - Jan 13 2016

Bibliographical note

Funding Information:
We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children''s Discovery Institute of Washington University and St. Louis Children''s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.).

Funding Information:
We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.).

Publisher Copyright:
© 2016 Elsevier Inc.

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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, H. W. (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

Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. / Lu, Qun; Yokoyama, Christine C.; Williams, Jesse W.; Baldridge, Megan T.; Jin, Xiaohua; Desrochers, Brittany; Bricker, Traci; Wilen, Craig B.; Bagaitkar, Juhi; Loginicheva, Ekaterina; Sergushichev, Alexey; Kreamalmeyer, Darren; Keller, Brian C.; Zhao, Yan; Kambal, Amal; Green, Douglas R.; Martinez, Jennifer; Dinauer, Mary C.; Holtzman, Michael J.; Crouch, Erika C.; Beatty, Wandy; Boon, Adrianus C.M.; Zhang, Hong; Randolph, Gwendalyn J.; Artyomov, Maxim N.; Virgin, Herbert W.

In: Cell Host and Microbe, Vol. 19, No. 1, 13.01.2016, p. 102-113.

Research output: Contribution to journal › Article › peer-review

Lu, Q, Yokoyama, CC, Williams, JW, Baldridge, MT, Jin, X, Desrochers, B, Bricker, T, Wilen, CB, Bagaitkar, J, Loginicheva, E, Sergushichev, A, Kreamalmeyer, D, Keller, BC, Zhao, Y, Kambal, A, Green, DR, Martinez, J, Dinauer, MC, Holtzman, MJ, Crouch, EC, Beatty, W, Boon, ACM, Zhang, H, Randolph, GJ, Artyomov, MN & Virgin, HW 2016, 'Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis', Cell Host and Microbe, vol. 19, no. 1, pp. 102-113. https://doi.org/10.1016/j.chom.2015.12.011

Lu, Qun ; Yokoyama, Christine C. ; Williams, Jesse W. ; Baldridge, Megan T. ; Jin, Xiaohua ; Desrochers, Brittany ; Bricker, Traci ; Wilen, Craig B. ; Bagaitkar, Juhi ; Loginicheva, Ekaterina ; Sergushichev, Alexey ; Kreamalmeyer, Darren ; Keller, Brian C. ; Zhao, Yan ; Kambal, Amal ; Green, Douglas R. ; Martinez, Jennifer ; Dinauer, Mary C. ; Holtzman, Michael J. ; Crouch, Erika C. ; Beatty, Wandy ; Boon, Adrianus C.M. ; Zhang, Hong ; Randolph, Gwendalyn J. ; Artyomov, Maxim N. ; Virgin, Herbert W. / Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. In: Cell Host and Microbe. 2016 ; Vol. 19, No. 1. pp. 102-113.

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

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.",

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

note = "Funding Information: We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children''s Discovery Institute of Washington University and St. Louis Children''s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.). Funding Information: We thank Xinyu Wang and Stoyan Ivanov for technical assistance. This work was supported by NIH awards U19AI109725 (H.W.V.), U19AI070489 (M.J.H.), RO1AI111605 (M.J.H.), RO1HL121791 (M.J.H.), and AI049653 (G.J.R.) and training grants T32AI007163 (C.C.Y.), T32DK7296 (J.W.W.), T32CA009547 (M.T.B.), and T32HL07317 (B.C.K.). This work was also supported by the WM Keck Fellowship from Washington University (M.T.B.), Washington University School of Medicine (A.C.M.B.), the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital (M.C.D., J.B.), the Howard Hughes Medical Institute (H.Z.), and grant 2013CB910100 from the National Basic Research Program of China (H.Z.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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T1 - Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis

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AU - Williams, Jesse W.

AU - Baldridge, Megan T.

AU - Jin, Xiaohua

AU - Desrochers, Brittany

AU - Bricker, Traci

AU - Wilen, Craig B.

AU - Bagaitkar, Juhi

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AU - Green, Douglas R.

AU - Martinez, Jennifer

AU - Dinauer, Mary C.

AU - Holtzman, Michael J.

AU - Crouch, Erika C.

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

Abstract

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