title: Induction of macrophage death by clinical strains of Mycobacterium kansasii.
abstract: Mycobacterium kansasii is a facultative intracellular pathogen causing pulmonary disease in immunocompetent patients. Little is known about the host defense against M. kansasii and its intracellular survival strategy inside macrophages. In the present study, we obtained six clinical isolates from patients with M. kansasii pulmonary disease and investigated the intracellular growth and cytotoxic effects of M. kansasii inside mouse bone marrow-derived macrophages (BMDM) as well as cytokine secretion from BMDM. Interestingly, two isolates, SM-1 and 2693-20, displayed faster growth rates and higher levels of TNF-alpha secretion from macrophages when compared to the other strains. In addition, SM-1 and 2693-20 also induced massive cell death in BMDM and THP-1 acute monocytic leukemia cells, while the slow growing strains induced significantly lower levels of cell death. This cytotoxicity was mainly caused by necrosis, not apoptosis and it was TNF-alpha-independent. Caspase inhibitors failed to block M. kansasii-induced macrophage death. In addition, necrosis caused by the fast growing strains was accompanied by the loss of mitochondrial membrane potential (DeltaPsi(m)). When dissipation of DeltaPsi(m) was inhibited by the classical mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA), macrophage necrosis was reduced. These results suggest that clinical isolates of M. kansasii that grow faster in macrophages induce higher levels of necrosis in a DeltaPsi(m) loss-dependent manner.
authors.affiliation: Department of Microbiology, College of Medicine, Chungnam National University, 6 Munwha-Dong, Jung-Ku, Daejeon 301-747, Republic of Korea. hsmy1558@hanmail.net
authors.forename: Hosung
authors.initials: H
authors.lastname: Sohn
authors.forename: Kwang-Wook
authors.initials: KW
authors.lastname: Kim
authors.forename: Hyun Bae
authors.initials: HB
authors.lastname: Kang
authors.forename: Choul-Jae
authors.initials: CJ
authors.lastname: Won
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.forename: Byungsoo
authors.initials: B
authors.lastname: Lee
authors.forename: O Jung
authors.initials: OJ
authors.lastname: Kwon
authors.forename: Won-Jung
authors.initials: WJ
authors.lastname: Koh
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D019909:Mycobacterium kansasii / Q000254:growth & development / Q000472:pathogenicity*; D009336:Necrosis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases