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

Abstract

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.

Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities

“…Thus, mtROS was measured in BMDMs by MitoSOX Red, a fluorescent probe for mtROS ( Bulua et al, 2011 ). Similar to the previous findings ( Kim Y. J. et al, 2020 ), Mabs-R infection of BMDMs led to an increase of mtROS production at 2 hpi, which was decreased with Rufomycin 4–7 treatment ( Figure 6A ). The relative fluorescent intensity level of MitoSOX was quantified to show that an increase of Rufomycin 4–7 dose gradually and significantly diminished the mtROS level of Mabs-R-infected BMDMs ( Figure 6B ).…”

“…However, to evaluate its antimicrobial effects in vivo , Rufomycin 4–7 was administered to the Mabs-R-infected mice. By using the Mabs-R pulmonary infection model established in the previous work ( Kim Y. J. et al, 2020 ), it was confirmed that Rufomycin 4–7 treatment significantly decreased Mabs-R survival in the mouse lungs at 21 days post-infection (dpi) ( Figure 1A ). In addition, Rufomycin 4–7 administration significantly inhibited Mabs-R-mediated inflammatory reactions in the mouse lungs.…”

“…A previous study showed that exaggerated pathologic inflammation played a detrimental role in antimicrobial host defense against Mabs-R infection ( Kim Y. J. et al, 2020 ). To explore whether Rufomycin 4–7 ameliorated inflammatory responses and promoted protective immune functions, the relative expressions of cytokines and chemokines were examined in the Mabs-infected BMDMs.…”

“…The increased mitochondrial oxidative stresses are associated with hyperinflammatory responses and detrimental function in antimicrobial effects during Mabs-R infection ( Kim Y. J. et al, 2020 ). Thus, mtROS was measured in BMDMs by MitoSOX Red, a fluorescent probe for mtROS ( Bulua et al, 2011 ).…”

“…Mabs-R also accesses cytosols through phagosomal rupture, thereby promoting type I interferon (IFN) release, cell death, and cell-to-cell spreading ( Kim B. R. et al, 2019 ). More recently, Mabs-R-susceptible sirtuin 3 mice induced mitochondrial damage and pathological inflammation during infection ( Kim Y. J. et al, 2020 ). These studies enabled the investigation of a new strategy for anti-Mabs drugs that employ a bidirectional mode, not only through antimicrobial activity but also via host immune modulation.…”