Researchers Identify the Evading Mechanism of Mycobacterium Tuberculosis to Escape Death

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Researchers from University of Alabama at Birmingham identify the mechanism of tuberculosis bacteria that are capable of escaping destruction by lung macrophages

The research led by Michael Niederweis, Ph.D. and professor of microbiology at UAB reveals patient-targeted strategies to treat tuberculosis. According to a report by World Health Organization in 2012, this infectious disease causes 1.4 million deaths and infects over 10 million each year. The team identified the first toxin ever found in tuberculosis in 2015. The tuberculosis necrotizing toxin (TNT) is the first of the novel class of previously unrecognized toxins present in acterial and fungal species. The team observed that TNT enzymatically hydrolyzes nicotinamide adenine dinucleotide (NAD) +, a vital coenzyme that is involved in redox reactions in all living cells, which in turn leads to necrotic cell death of the macrophage. This necrotic death releases the M. tuberculosis bacteria to infect more cells and hijack the macrophage away from its normal route to destroy engulfed bacteria. Eventually TNT controls the fate of infected macrophages by assisting the battle between M. tuberculosis and the human immune system. The research was published in Cell Press on June 12, 2018.

Macrophages have necroptosis genes that can be activated by the immune system. These genes have canonical pathway to program necrosis, which is a programmed inflammatory cell death. The researchers observed that depletion of NAD+ by TNT hydrolysis activated RIPK3 and MLKL mediators of necroptosis genes, while bypassing two upstream components of the pathway. Meanwhile, mitochondria became depolarized, and synthesis of ATP was impaired. However, depleted NAD+ levels in healthy macrophages by inhibiting an enzyme in the NAD+ salvage pathway led to necrosis through the RIPK3 and MLKL pathway. This was sufficient to induce necroptosis. It was observed that adding nicotinamide to the cell culture of infected macrophages enhanced its viability threefold. Furthermore, adding compounds to protect mitochondria increased the rate of mitochondrial respiration or prevented cell death. Use of FDA-approved drugs that decrease necroptosis are expected to treat tuberculosis.

 

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