Induction of macrophage death by clinical strains of Mycobacterium kansasii.
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.
Sohn
Hosung
H
Department of Microbiology, College of Medicine, Chungnam National University, 6 Munwha-Dong, Jung-Ku, Daejeon 301-747, Republic of Korea. hsmy1558@hanmail.net
Kim
Kwang-Wook
KW
Kang
Hyun Bae
HB
Won
Choul-Jae
CJ
Kim
Woo Sik
WS
Lee
Byungsoo
B
Kwon
O Jung
OJ
Koh
Won-Jung
WJ
Shin
Sung Jae
SJ
Kim
Hwa-Jung
HJ
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
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases