Lee Jae Seung, Dittmar Mark, Miller Jesse, Li Minghua, Ayyanathan Kasirajan, Ferretti Max, Hulahan Jesse, Whig Kanupriya, Etwebi Zienab, Griesman Trevor, Schultz David C, Cherry Sara
bioRxiv. 2023 Nov 16:2023.11.13.566859. doi: 10.1101/2023.11.13.566859.
SARS-CoV-2 emerged, and is evolving to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling activated only in bystander cells. This balance of innate activation and viral evasion has important consequences, but the pathways involved are incompletely understood. Here we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons, and thus permissivity to infection. Mechanistically, autophagy genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, upon loss of autophagy increased MAVS overcomes ORF9b-mediated antagonism suppressing infection. This has led to the evolution of SARS-CoV-2 variants to express higher levels of ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of autophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）出现并正在进化，以有效地感染全球人类。SARS-CoV-2逃避早期固有识别，干扰素信号仅在旁观者细胞中被激活。这种固有激活和病毒逃避的平衡具有重要后果，但其中涉及的途径尚未完全了解。在这里，我们发现自噬基因调节固有免疫信号，影响干扰素的基础设定点，从而影响感染的易感性。从机制上讲，自噬基因负向调节线粒体抗病毒信号蛋白（MAVS），而MAVS的这种低基础水平被SARS-CoV-2的开放阅读框9b（ORF9b）有效拮抗，从而阻断受感染细胞中的干扰素激活。然而，自噬缺失后MAVS的增加克服了ORF9b介导的拮抗作用，抑制了感染。这导致SARS-CoV-2变体进化为表达更高水平的ORF9b，使SARS-CoV-2能够在MAVS信号增加的条件下复制。总之，我们发现自噬在固有免疫调节中起关键作用，并揭示了SARS-CoV-2 ORF9b克服宿主防御的进化轨迹。
