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
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2025 Jan 28;44(1):115115. doi: 10.1016/j.celrep.2024.115115. Epub 2024 Dec 20.
SARS-CoV-2 emerged, and continues to evolve, to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling occurring only in bystander cells. How the virus continues to evolve in the face of innate responses 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 (mitophagy) 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, loss of autophagy increased MAVS and overcomes ORF9b-mediated antagonism. This has driven the evolution of SARS-CoV-2 to express more ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of mitophagy 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）出现并持续进化，从而能够在全球范围内高效感染人类。SARS-CoV-2逃避早期固有识别，干扰素信号传导仅在旁观者细胞中发生。面对固有免疫反应，该病毒如何持续进化具有重要影响，但其中涉及的途径尚未完全了解。在此，我们发现自噬基因调节固有免疫信号传导，影响干扰素的基础设定点，进而影响对感染的易感性。从机制上讲，自噬（线粒体自噬）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，自噬缺失会增加MAVS并克服ORF9b介导的拮抗作用。这促使SARS-CoV-2进化以表达更多的ORF9b，使SARS-CoV-2能够在MAVS信号增强的条件下复制。总之，我们发现线粒体自噬在固有免疫调节中起关键作用，并揭示了SARS-CoV-2的ORF9b克服宿主防御的进化轨迹。
