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

摘要

巨自噬/自噬基因EPG5的突变导致 Vici 综合征，这是一种以联合免疫缺陷为特征的人类遗传病。以前，我们发现epg5 ^-/-小鼠在 IL1B/IL-1β 和 TNF/TNFα 介导的肺部表现出过度炎症，导致对流感的抵抗力。在这里，我们发现Epg5的破坏导致对包括诺如病毒和轮状病毒在内的多种肠道病毒的保护。基因表达分析揭示了 IFNL/IFN-λ 反应基因是一个关键的改变。此外，缺乏Epg5的小鼠表现出肠道微生物群的显着改变。令人惊讶的是，无菌小鼠研究表明Epg5-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 信号作为epg5 ^-/-小鼠肠道病毒抗性的主要介质，而不是微生物菌群失调的主要介质。这项研究揭示了自噬基因Epg5通过调节肠道 IFNL 反应在宿主生物保护中的重要作用，出人意料地独立于微生物群。

缩写：CTNNB1：连环蛋白（钙粘蛋白相关蛋白），β 1；DAPI：4',6-二脒基-2-苯基吲哚；EPG5：异位 P 颗粒自噬蛋白 5 同系物（线虫）；FT：粪便移植；IFI44：干扰素诱导蛋白 44；IFIT1：干扰素诱导蛋白与四肽重复序列 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 1 β；ISG：干扰素刺激基因；GF：无菌；LEfSe：线性判别分析效应量；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MNoV：小鼠诺如病毒；MX2：MX 动力蛋白样 GTPase 2；OAS1A：2'-5'寡聚腺苷酸合成酶 1A；RV：轮状病毒；SPF：无特定病原体；SQSTM1/p62：螯合体 1；STAT1：信号转导和转录激活因子 1；STING1：干扰素反应刺激物 cGAMP 相互作用物 1；TBK1：TANK 结合激酶 1；TNF/TNFα：肿瘤坏死因子