PMID- 32835604 OWN - NLM STAT- MEDLINE DCOM- 20210719 LR - 20210719 IS - 2150-5608 (Electronic) IS - 2150-5594 (Print) IS - 2150-5594 (Linking) VI - 11 IP - 1 DP - 2020 Dec TI - Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis. PG - 1225-1239 LID - 10.1080/21505594.2020.1809961 [doi] AB - 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. FAU - Kim, Young Jae AU - Kim YJ AD - Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea. AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. FAU - Lee, Sang-Hee AU - Lee SH AD - Center for Research Equipment, Korea Basic Science Institute , Cheongju, Chungbuk, South Korea. FAU - Jeon, Sang Min AU - Jeon SM AD - Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea. AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. FAU - Silwal, Prashanta AU - Silwal P AUID- ORCID: 0000-0002-8332-024X AD - Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea. AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. FAU - Seo, Ju-Young AU - Seo JY AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea. FAU - Hanh, Bui Thi Bich AU - Hanh BTB AD - Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University , Jinju, Korea. AD - Division of Applied Life Science (Bk21plus Program), Gyeongsang National University , Jinju, Korea. FAU - Park, June-Woo AU - Park JW AD - Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology , Jinju, Korea. AD - Human and Environmental Toxicology Program, Korea University of Science and Technology (UST) , Daejeon, Korea. FAU - Whang, Jake AU - Whang J AUID- ORCID: 0000-0003-4444-508X AD - Korea Mycobacterium Resource Center (KMRC) & Basic Research Section, The Korean Institute of Tuberculosis (KIT) 168-5 , Cheongju-si, Chungcheongbuk-do, Republic of Korea. FAU - Lee, Min Joung AU - Lee MJ AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - Department of Biochemistry, Chungnam National University College of Medicine , Korea. FAU - Heo, Jun Young AU - Heo JY AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - Department of Biochemistry, Chungnam National University College of Medicine , Korea. AD - Department of Medical Science, Chungnam National University College of Medicine , Daejeon, Korea. FAU - Kim, Soon Ha AU - Kim SH AD - MitoImmune Therapeutics, Inc ., Ganhnam-gu, Seoul, Korea. FAU - Kim, Jin-Man AU - Kim JM AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - Department of Pathology; Chungnam National University College of Medicine , Korea. FAU - Song, Gyu Yong AU - Song GY AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - College of Pharmacy, Chungnam National University , Daejeon, Republic of Korea. FAU - Jang, Jichan AU - Jang J AD - Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University , Jinju, Korea. FAU - Jo, Eun-Kyeong AU - Jo EK AUID- ORCID: 0000-0001-7191-0587 AD - Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea. AD - Infection Control Convergence Research Center, Chungnam National University College of Medicine , Daejeon, Korea. AD - Department of Medical Science, Chungnam National University College of Medicine , Daejeon, Korea. LA - eng PT - Journal Article PL - United States TA - Virulence JT - Virulence JID - 101531386 RN - 0 (Reactive Oxygen Species) RN - 0 (Sirt3 protein, mouse) RN - EC 3.5.1.- (Sirtuin 3) SB - IM MH - Animals MH - Gene Expression Regulation MH - *Homeostasis MH - *Host-Pathogen Interactions MH - Macrophages/microbiology/physiology MH - Male MH - Mice MH - Mitochondria/*physiology MH - Mycobacterium Infections, Nontuberculous/*prevention & control MH - Mycobacterium abscessus/growth & development/pathogenicity MH - Oxidative Stress MH - Reactive Oxygen Species MH - Sirtuin 3/*genetics/metabolism MH - Zebrafish/microbiology PMC - PMC7549921 OTO - NOTNLM OT - Mycobacterium abscessus OT - host-directed therapy OT - mitochondrial reactive oxygen species OT - resveratrol OT - sirtuin 3 COIS- S.-H. Kim is an inventor of MIT-001, the necrosis inhibitor (patent number, KR2008-0080519). The other authors declare no competing interests. EDAT- 2020/08/25 06:00 MHDA- 2021/07/20 06:00 PMCR- 2020/09/09 CRDT- 2020/08/25 06:00 PHST- 2020/08/25 06:00 [pubmed] PHST- 2021/07/20 06:00 [medline] PHST- 2020/08/25 06:00 [entrez] PHST- 2020/09/09 00:00 [pmc-release] AID - 1809961 [pii] AID - 10.1080/21505594.2020.1809961 [doi] PST - ppublish SO - Virulence. 2020 Dec;11(1):1225-1239. doi: 10.1080/21505594.2020.1809961.