Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.
Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea.
Virulence. 2020 Dec;11(1):1225-1239. doi: 10.1080/21505594.2020.1809961.
The global incidence of (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.
（Mabc）是一种快速生长的非结核分枝杆菌菌株，可导致治疗耐药性肺部疾病，其在全球的发病率正在上升。尽管如此，宿主中能够防止感染的因素在很大程度上仍是未知的。在这项研究中，我们发现，线粒体蛋白去乙酰化酶 SIRT3 在宿主防御 Mabc 感染中起着关键作用。Mabc 降低了巨噬细胞中的 SIRT3 并上调了线粒体氧化应激。SIRT3 缺乏导致细菌负荷增加、组织病理学和线粒体损伤以及 Mabc 感染期间的病理性炎症。线粒体活性氧清除剂的给药显著降低了体内 Mabc 的负担和过度炎症，并诱导了感染肺部中的 SIRT3 表达。值得注意的是，SIRT3 激动剂（白藜芦醇）显著降低了小鼠和斑马鱼中的 Mabc 生长并减轻了炎症，表明 SIRT3 在后生动物宿主防御中起着关键作用。总的来说，这些数据强烈表明，SIRT3 通过控制线粒体动态平衡是针对 Mabc 感染的宿主导向治疗靶标。
