Lee Sanghyun, Kalugotla Gowri, Ingle Harshad, Rodgers Rachel, Wu Chunyan, Wang Yating, Li Yuhao, Yang Xia, Zhang Jin, Borella Nicolette R, Deng Hongju, Droit Lindsay, Hill Ryan, Peterson Stefan T, Desai Chandni, Lawrence Dylan, Lu Qun, Baldridge Megan T
Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Autophagy. 2022 May;18(5):1062-1077. doi: 10.1080/15548627.2021.1968607. Epub 2021 Sep 14.
Mutations in the macroautophagy/autophagy gene are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that 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 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 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate 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 mice. This study unveils an important role, unexpectedly independent of the microbiota, for autophagy gene in host organism protection by modulating intestinal IFNL responses. 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.
自噬基因的突变是维西综合征的病因，这是一种以联合免疫缺陷为特征的人类遗传疾病。此前，我们发现自噬基因缺陷的小鼠肺部会出现由IL1B/IL-1β和TNF/TNFα介导的过度炎症，从而对流感产生抵抗力。在此，我们发现自噬基因的缺失可预防包括诺如病毒和轮状病毒在内的多种肠道病毒。基因表达分析显示IFNL/IFN-λ反应基因是关键的改变因素。此外，缺乏自噬基因的小鼠肠道微生物群有显著变化。令人惊讶的是，无菌小鼠研究表明，肠道和肺部的相关炎症与微生物群无关。遗传学研究支持IFNL信号传导是自噬基因缺陷小鼠抵抗肠道病毒的主要介质，但不是微生物群失调的主要介质。本研究揭示了自噬基因在通过调节肠道IFNL反应保护宿主生物体方面发挥的重要作用，这一作用出人意料地独立于微生物群。CTNNB1：连环蛋白（钙黏着蛋白相关蛋白），β1；DAPI：4',6-二脒基-2-苯基吲哚；EPG5：异位P颗粒自噬蛋白5同源物（秀丽隐杆线虫）；FT：粪便移植；IFI44：干扰素诱导蛋白44；IFIT1：具有四肽重复序列的干扰素诱导蛋白1；IFNG/IFN-γ：干扰素γ；IFNL/IFN-λ：干扰素λ；IFNLR1：干扰素λ受体1；IL1B/IL-1β：白细胞介素1β；ISG：干扰素刺激基因；GF：无菌；LEfSe：线性判别分析效应大小；MAP1LC3/LC3：微管相关蛋白1轻链3；MNoV：鼠诺如病毒；MX2：MX动力蛋白样GTP酶2；OAS1A：2'-5'寡腺苷酸合成酶1A；RV：轮状病毒；SPF：无特定病原体；SQSTM1/p62：聚集体蛋白1；STAT1：信号转导和转录激活因子1；STING1：干扰素反应cGAMP相互作用蛋白1；TBK1：TANK结合激酶1；TNF/TNFα：肿瘤坏死因子
