Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota

Sanghyun Lee; Gowri Kalugotla; Harshad Ingle; Rachel Rodgers; Chunyan Wu; Yating Wang; Yuhao Li; Xia Yang; Jin Zhang; Nicolette R. Borella; Hongju Deng; Lindsay Droit; Ryan Hill; Stefan T. Peterson; Chandni Desai; Dylan Lawrence; Qun Lu; Megan T. Baldridge

doi:10.1080/15548627.2021.1968607

Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota

Sanghyun Lee
, Gowri Kalugotla
, Harshad Ingle
, Rachel Rodgers
, Chunyan Wu
, Yating Wang
, Yuhao Li
, Xia Yang
, Jin Zhang
, Nicolette R. Borella
, Hongju Deng
, Lindsay Droit
, Ryan Hill
, Stefan T. Peterson
, Chandni Desai
, Dylan Lawrence
, Qun Lu
, Megan T. Baldridge

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

10 Scopus citations

Abstract

Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5^−/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1β and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5^−/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses. Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4′,6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1β: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2’-5’ oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.

Original language	English
Pages (from-to)	1062-1077
Number of pages	16
Journal	Autophagy
Volume	18
Issue number	5
DOIs	https://doi.org/10.1080/15548627.2021.1968607
State	Published - 2022

Keywords

Antiviral
Epg5
IFN-λ
microbiota
norovirus
rotavirus

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10.1080/15548627.2021.1968607

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Lee, S., Kalugotla, G., Ingle, H., Rodgers, R., Wu, C., Wang, Y., Li, Y., Yang, X., Zhang, J., Borella, N. R., Deng, H., Droit, L., Hill, R., Peterson, S. T., Desai, C., Lawrence, D., Lu, Q., & Baldridge, M. T. (2022). Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota. Autophagy, 18(5), 1062-1077. https://doi.org/10.1080/15548627.2021.1968607

@article{1c5f8ab750df4231a356978fa4b351f8,

title = "Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota",

abstract = "Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5−/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1β and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5−/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses. Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4′,6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1β: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2{\textquoteright}-5{\textquoteright} oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.",

keywords = "Antiviral, Epg5, IFN-λ, microbiota, norovirus, rotavirus",

author = "Sanghyun Lee and Gowri Kalugotla and Harshad Ingle and Rachel Rodgers and Chunyan Wu and Yating Wang and Yuhao Li and Xia Yang and Jin Zhang and Borella, \{Nicolette R.\} and Hongju Deng and Lindsay Droit and Ryan Hill and Peterson, \{Stefan T.\} and Chandni Desai and Dylan Lawrence and Qun Lu and Baldridge, \{Megan T.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Informa UK Limited, trading as Taylor \& Francis Group.",

year = "2022",

doi = "10.1080/15548627.2021.1968607",

language = "English",

volume = "18",

pages = "1062--1077",

journal = "Autophagy",

issn = "1554-8627",

number = "5",

}

Lee, S, Kalugotla, G, Ingle, H, Rodgers, R, Wu, C, Wang, Y, Li, Y, Yang, X, Zhang, J, Borella, NR, Deng, H, Droit, L, Hill, R, Peterson, ST, Desai, C, Lawrence, D, Lu, Q & Baldridge, MT 2022, 'Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota', Autophagy, vol. 18, no. 5, pp. 1062-1077. https://doi.org/10.1080/15548627.2021.1968607

TY - JOUR

T1 - Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota

AU - Lee, Sanghyun

AU - Kalugotla, Gowri

AU - Ingle, Harshad

AU - Rodgers, Rachel

AU - Wu, Chunyan

AU - Wang, Yating

AU - Li, Yuhao

AU - Yang, Xia

AU - Zhang, Jin

AU - Borella, Nicolette R.

AU - Deng, Hongju

AU - Droit, Lindsay

AU - Hill, Ryan

AU - Peterson, Stefan T.

AU - Desai, Chandni

AU - Lawrence, Dylan

AU - Lu, Qun

AU - Baldridge, Megan T.

PY - 2022

Y1 - 2022

N2 - Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5−/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1β and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5−/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses. Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4′,6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1β: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2’-5’ oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.

AB - Mutations in the macroautophagy/autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that epg5−/- mice exhibit hyperinflammation in the lungs mediated by IL1B/IL-1β and TNF/TNFα, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFNL/IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFNL signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis, in epg5−/- mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene Epg5 in host organism protection by modulating intestinal IFNL responses. Abbreviations: CTNNB1: catenin (cadherin associated protein), beta 1; DAPI: 4′,6-diamidino-2-phenylindole; EPG5: ectopic P-granules autophagy protein 5 homolog (C. elegans); FT: fecal transplant; IFI44: interferon-induced protein 44; IFIT1: interferon-induced protein with tetratricopeptide repeats 1; IFNG/IFN-γ: interferon gamma; IFNL/IFN-λ: interferon lambda; IFNLR1: interferon lambda receptor 1; IL1B/IL-1β: interleukin 1 beta; ISG: interferon stimulated gene; GF: germ-free; LEfSe: linear discriminant analysis effect size; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MNoV: murine norovirus; MX2: MX dynamin-like GTPase 2; OAS1A: 2’-5’ oligoadenylate synthetase 1A; RV: rotavirus; SPF: specific-pathogen free; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1; TNF/TNFα: tumor necrosis factor.

KW - Antiviral

KW - Epg5

KW - IFN-λ

KW - microbiota

KW - norovirus

KW - rotavirus

UR - https://www.scopus.com/pages/publications/85114853818

U2 - 10.1080/15548627.2021.1968607

DO - 10.1080/15548627.2021.1968607

M3 - Article

C2 - 34520306

AN - SCOPUS:85114853818

SN - 1554-8627

VL - 18

SP - 1062

EP - 1077

JO - Autophagy

JF - Autophagy

IS - 5

ER -

Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota

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Keywords

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