Induction of macrophage death by clinical strains of Mycobacterium kansasii
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Published on: January 9, 2019
Hosung Sohn1, Kwang-Wook Kim, Hyun Bae Kang
1Department of Microbiology, College of Medicine, Chungnam National University, 6 Munwha-Dong, Jung-Ku, Daejeon 301-747, Republic of Korea. hsmy1558@hanmail.net
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.
Insights
Fast-growing Mycobacterium kansasii strains cause significant macrophage necrosis, independent of TNF-alpha. This cell death is linked to mitochondrial membrane potential loss, suggesting a novel virulence mechanism for this pulmonary pathogen.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Mycobacterium kansasii causes pulmonary disease in immunocompetent individuals.
- Host defense mechanisms and intracellular survival strategies of M. kansasii remain poorly understood.
- Macrophages play a critical role in controlling intracellular bacterial infections.
Purpose of the Study:
- To investigate the intracellular growth and cytotoxic effects of clinical M. kansasii isolates in macrophages.
- To analyze cytokine secretion and cell death pathways induced by M. kansasii.
- To elucidate the mechanism of M. kansasii-induced macrophage death.
Main Methods:
- Isolation and characterization of six clinical M. kansasii strains.
- In vitro infection of mouse bone marrow-derived macrophages (BMDM) and THP-1 cells.
- Measurement of bacterial growth, cytokine (TNF-alpha) secretion, and cell viability (necrosis, apoptosis).
- Assessment of mitochondrial membrane potential (DeltaPsi(m)) and inhibition studies using cyclosporine A (CsA).
Main Results:
- Two M. kansasii isolates (SM-1, 2693-20) exhibited faster intracellular growth and higher TNF-alpha secretion compared to other strains.
- Fast-growing isolates induced massive necrosis in BMDM and THP-1 cells, while slow-growing strains caused minimal cell death.
- M. kansasii-induced necrosis was TNF-alpha-independent and caspase-independent.
- Necrosis correlated with loss of mitochondrial membrane potential (DeltaPsi(m)), which was partially inhibited by CsA.
Conclusions:
- Faster-growing clinical isolates of M. kansasii induce significant macrophage necrosis.
- This necrosis is dependent on the loss of mitochondrial membrane potential (DeltaPsi(m)).
- M. kansasii employs a virulence strategy involving mitochondrial dysfunction and necrosis in host macrophages.
