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

7 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 - http://www.scopus.com/inward/record.url?scp=85114853818&partnerID=8YFLogxK

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

Abstract

Keywords

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