title: Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth.
abstract: Mycobacterium avium complex induces macrophage apoptosis. However, the M. avium components that inhibit or trigger apoptosis and their regulating mechanisms remain unclear. We recently identified the immunodominant MAV2054 protein by fractionating M. avium culture filtrate protein by multistep chromatography; this protein showed strong immuno-reactivity in M. avium complex pulmonary disease and in patients with tuberculosis. Here, we investigated the biological effects of MAV2054 on murine macrophages. Recombinant MAV2054 induced caspase-dependent macrophage apoptosis. Enhanced reactive oxygen species production and JNK activation were essential for MAV2054-mediated apoptosis and MAV2054-induced interleukin-6, tumour necrosis factor, and monocyte chemoattractant protein-1 production. MAV2054 was targeted to the mitochondrial compartment of macrophages treated with MAV2054 and infected with M. avium. Dissipation of the mitochondrial transmembrane potential (ΔΨm) and depletion of cytochrome c also occurred in MAV2054-treated macrophages. Apoptotic response, reactive oxygen species production, and ΔΨmcollapse were significantly increased in bone marrow-derived macrophages infected with Mycobacterium smegmatis expressing MAV2054, compared to that in M. smegmatis control. Furthermore, MAV2054 expression suppressed intracellular growth of M. smegmatis and increased the survival rate of M. smegmatis-infected mice. Thus, MAV2054 induces apoptosis via a mitochondrial pathway in macrophages, which may be an innate cellular response to limit intracellular M. avium multiplication.
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Kang-In
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Jake
authors.initials: J
authors.lastname: Whang
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Han-Gyu
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Yeo-Jin
authors.initials: YJ
authors.lastname: Son
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Haet Sal
authors.initials: HS
authors.lastname: Jeon
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Back
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Hye-Soo
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Seungwha
authors.initials: S
authors.lastname: Paik
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Jeong-Kyu
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Chul Hee
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.|Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009162:Mycobacterium avium / Q000378:metabolism* / Q000502:physiology*; D020102:Mycobacterium smegmatis / Q000378:metabolism / Q000502:physiology; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c