Barthez Marine, Xue Biyun, Zheng Jian, Wang Yifei, Song Zehan, Mu Wei-Chieh, Wang Chih-Ling, Guo Jiayue, Yang Fanghan, Ma Yuze, Wei Xuetong, Ye Chengjin, Sims Nicholas, Martinez-Sobrido Luis, Perlman Stanley, Chen Danica
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
Cell Rep. 2025 Apr 22;44(4):115562. doi: 10.1016/j.celrep.2025.115562. Epub 2025 Apr 11.
Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.
衰老对2019冠状病毒病（COVID-19）的易感性仍知之甚少。在此，我们发现，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染缺乏SIRT2（一种胞质NAD依赖性脱乙酰酶）的老年小鼠会引发更严重的疾病，并显示死亡率增加，而用NAD增强剂78c治疗可保护老年小鼠免受致命感染。从机制上讲，我们证明SIRT2调节环状GMP-AMP合酶（cGAS，一种胞质DNA免疫传感器）的乙酰化，并抑制与衰老相关的cGAS激活和炎症。此外，我们表明，SARS-CoV-2感染诱导的炎症至少部分由ORF3a介导，ORF3a触发线粒体DNA释放和cGAS激活。总的来说，我们的研究揭示了衰老对COVID-19易感性的分子基础，并提出了保护老年人群免受严重SARS-CoV-2感染的治疗方法。
