• 作者： Mi-Hyun Lee, Hye Lin Kim, Hyejun Seo, Sangkwon Jung & Bum-Joon Kim
• 作者服務機構： 1.BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea 2.Cancer Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea 3.Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea 4.Department of Microbiology and Immunology, College of Medicine, Seoul National University, 103 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea 5.Liver Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea 6.Seoul National University Medical Research Center (SNUMRC), Seoul, 03080, Republic of Korea
• 中文摘要：
• 英文摘要：
  Background
  Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), and its pathogenicity is associated with its ability to evade the host defense system. The secretory form of the chorismate mutase of M. tuberculosis (TBCM, encoded by Rv1885c) is assumed to play a key role in the pathogenesis of TB; however, the mechanism remains unknown.
  
  Methods
  A tbcm deletion mutant (B∆tbcm) was generated by targeted gene knockout in BCG to investigate the pathogenic role of TBCM in mice or macrophages. We compared the pathogenesis of B∆tbcm and wild-type BCG in vivo by measuring the bacterial clearance rate and the degree of apoptosis. Promotion of the intrinsic apoptotic pathway was evaluated in infected bone marrow-derived macrophages (BMDMs) by measuring apoptotic cell death, loss of mitochondrial membrane potential and translocation of pore-forming proteins. Immunocytochemistry, western blotting and real-time PCR were also performed to assess the related protein expression levels after infection. Furthermore, these findings were validated by complementation of tbcm in BCG.
  
  Results
  Deletion of the tbcm gene in BCG leads to reduced pathogenesis in a mouse model, compared to wild type BCG, by promoting apoptotic cell death and bacterial clearance. Based on these findings, we found that intrinsic apoptosis and mitochondrial impairment were promoted in B∆tbcm-infected BMDMs. B∆tbcm down-regulates the expression of Bcl-2, which leads to mitochondrial outer membrane permeabilization (MOMP), culminating in cytochrome c release from mitochondria. Consistent with this, transcriptome profiling also indicated that B∆tbcm infection is more closely related to altered mitochondrial-related gene expression than wild-type BCG infection, suggesting an inhibitory role of TBCM in mitochondrial dysfunction. Moreover, genetic complementation of B∆tbcm (C∆tbcm) restored its capacity to inhibit mitochondria-mediated apoptotic cell death.
  
  Conclusions
  Our findings demonstrate the contribution of TBCM to bacterial survival, inhibiting intrinsic apoptotic cell death of macrophages as a virulence factor of M. tuberculosis complex (MTBC) strains, which could be a potential target for the development of TB therapy.
• 中文關鍵字：
• 英文關鍵字： M. bovis BCG, M. tuberculosis, Mycobacterium tuberculosis chorismate mutase (TBCM), Rv1885c, Mitochondrial dysfunction, Intrinsic apoptosis, Macrophages, Deletion mutant, Virulence factor