Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

Virulence

Gyu Yong Song¹  Eun-Kyeong Jo¹  Min Joung Lee¹  Ju-Young Seo¹  Sang Min Jeon¹  Jin-Man Kim¹  Prashanta Silwal¹  Jun Young Heo¹  Young Jae Kim¹  Sang-Hee Lee²  June-Woo Park³  Soon Ha Kim⁴  Bui Thi Bich Hanh⁵  Jichan Jang⁵  Jake Whang⁶ 

[1] Chungnam National University College of Medicine;Korea Basic Science Institute;Korea Institute of Toxicology;MitoImmune Therapeutics, Inc;Research Institute of Life Science, Gyeongsang National University;The Korean Institute of Tuberculosis (KIT) 168-5;

关键词: mycobacterium abscessus;    sirtuin 3;    mitochondrial reactive oxygen species;    resveratrol;    host-directed therapy;   

DOI  :  10.1080/21505594.2020.1809961

来源: DOAJ

【 摘 要 】

The global incidence of Mycobacterium abscessus (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.

【 授权许可】

Unknown