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

Virulence

Sang-Hee Lee¹  June-Woo Park²  Young Jae Kim³  Prashanta Silwal³  Sang Min Jeon³  Eun-Kyeong Jo⁴  Gyu Yong Song⁵  Ju-Young Seo⁵  Min Joung Lee⁶  Jun Young Heo⁷  Jin-Man Kim⁸  Jake Whang⁹  Soon Ha Kim^1,10  Jichan Jang^1,11  Bui Thi Bich Hanh^1,12 

[1] Center for Research Equipment, Korea Basic Science Institute, Cheongju, Chungbuk, South Kore;Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology, Jinju, Kore;Human and Environmental Toxicology Program, Korea University of Science and Technology (UST), Daejeon, Kore;Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;College of Pharmacy, Chungnam National University, Daejeon, Republic of Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;Department of Biochemistry, Chungnam National University College of Medicine, Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;Department of Biochemistry, Chungnam National University College of Medicine, Kore;Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Kore;Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, Kore;Department of Pathology; Chungnam National University College of Medicine, Kore;Korea Mycobacterium Resource Center (KMRC) & Basic Research Section, The Korean Institute of Tuberculosis (KIT) 168-5, Cheongju-si, Chungcheongbuk-do, Republic of Kore;MitoImmune Therapeutics, Inc., Ganhnam-gu, Seoul, Kore;Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju, Kore;Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju, Kore;Division of Applied Life Science (Bk21plus Program), Gyeongsang National University, Jinju, Kore;

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

DOI  :  10.1080/21505594.2020.1809961

来源: Taylor & Francis

【 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】

CC BY