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.
N1 - Funding Information:
This study was supported by NIH grants [R01 AI127552], [R01 AI139314], [R01 AI141478] (M.T.B.), [T32 HG000045] (D.L.) and [R00 AI141683] (S.L.), National Natural Science Foundation of China (NSFC) [32070745] (Q.L.), National Laboratory of Biomacromolecules [2020kf01], [2021kf09] (Q.L.), a Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital Interdisciplinary Research Initiative grant [MI-II-2019-790] and the Pew Biomedical Scholars Program (M.T.B.). We acknowledge the Washington University Gnotobiotic Core Facility for assistance with germ-free mouse generation and recolonization services, as well as the Washington University Transgenic, Knockout and Micro-Injection Core for assistance with generation of mouse embryos. We also acknowledge the Pulmonary Morphology Core for assistance with lung histology and the Washington University Center for Cellular Imaging for assistance with microscopy.
Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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 -