期刊
CELLULAR MICROBIOLOGY
卷 22, 期 1, 页码 -出版社
WILEY
DOI: 10.1111/cmi.13115
关键词
macrophages; necroptosis; nicotinamide adenine dinucleotide; reactive oxygen species; TNT
资金
- National Institute of Allergy and Infectious Diseases [AI121354]
Mycobacterium tuberculosis (Mtb) kills infected macrophages through necroptosis, a programmed cell death that enhances mycobacterial replication and dissemination. The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mtb in macrophages and induces necroptosis by NAD(+) hydrolysis. Here, we show that the catalytic activity of TNT triggers the production of reactive oxygen species (ROS) in Mtb-infected macrophages causing cell death and promoting mycobacterial replication. TNT induces ROS formation both by activating necroptosis and by a necroptosis-independent mechanism. Most of the detected ROS originate in mitochondria as a consequence of opening the mitochondrial permeability transition pore. However, a significant part of ROS is produced by mechanisms independent of TNT and necroptosis. Expressing only the tnt gene in Jurkat T-cells also induces lethal ROS formation indicating that these molecular mechanisms are not restricted to macrophages. Both the antioxidant N-acetyl-cysteine and replenishment of NAD(+) by providing nicotinamide reduce ROS levels in Mtb-infected macrophages, protect them from cell death, and restrict mycobacterial replication. Our results indicate that a host-directed therapy combining replenishment of NAD(+) with inhibition of necroptosis and/or antioxidants might improve the health status of TB patients and augment antibacterial TB chemotherapy.
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