The emerging role of gasotransmitters in the pathogenesis of tuberculosis.

Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen and the second largest contributor to global mortality caused by an infectious agent after HIV. In infected host cells, Mtb is faced with a harsh intracellular environment including hypoxia and the release of nitric oxide (NO) and carbon monoxide (CO) by immune cells. Hypoxia, NO and CO induce a state of in vitro dormancy where Mtb senses these gases via the DosS and DosT heme sensor kinase proteins, which in turn induce a set of ∼47 genes, known as the Mtb Dos dormancy regulon. On the contrary, both iNOS and HO-1, which produce NO and CO, respectively, have been shown to be important against mycobacterial disease progression. In this review, we discuss the impact of O2, NO and CO on Mtb physiology and in host responses to Mtb infection as well as the potential role of another major endogenous gas, hydrogen sulfide (H2S), in Mtb pathogenesis.

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis.

The mechanisms by which Mycobacterium tuberculosis (Mtb) maintains metabolic equilibrium to survive during infection and upon exposure to antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) and mycothiol (MSH) are the major redox buffers present in Mtb, but the contribution of EGT to Mtb redox homeostasis and virulence remains unknown. We report that Mtb WhiB3, a 4Fe-4S redox sensor protein, regulates EGT production and maintains bioenergetic homeostasis. We show that central carbon metabolism and lipid precursors regulate EGT production and that EGT modulates drug sensitivity. Notably, EGT and MSH are both essential for redox and bioenergetic homeostasis. Transcriptomic analyses of EGT and MSH mutants indicate overlapping but distinct functions of EGT and MSH. Last, we show that EGT is critical for Mtb survival in both macrophages and mice. This study has uncovered a dynamic balance between Mtb redox and bioenergetic homeostasis, which critically influences Mtb drug susceptibility and pathogenicity.

The Physiology and Genetics of Oxidative Stress in Mycobacteria.

During infection, Mycobacterium tuberculosis is exposed to a diverse array of microenvironments in the human host, each with its own unique set of redox conditions. Imbalances in the redox environment of the bacillus or the host environment serve as stimuli, which could regulate virulence. The ability of M. tuberculosis to evade the host immune response and cause disease is largely owing to the capacity of the mycobacterium to sense changes in its environment, such as host-generated gases, carbon sources, and pathological conditions, and alter its metabolism and redox balance accordingly for survival. In this article we discuss the redox sensors that are, to date, known to be present in M. tuberculosis, such as the Dos dormancy regulon, WhiB family, anti-σ factors, and MosR, in addition to the strategies present in the bacillus to neutralize free radicals, such as superoxide dismutases, catalase-peroxidase, thioredoxins, and methionine sulfoxide reductases, among others. M. tuberculosis is peculiar in that it appears to have a hierarchy of redox buffers, namely, mycothiol and ergothioneine. We discuss the current knowledge of their biosynthesis, function, and regulation. Ergothioneine is still an enigma, although it appears to have distinct and overlapping functions with mycothiol, which enable it to protect against a wide range of toxic metabolites and free radicals generated by the host. Developing approaches to quantify the intracellular redox status of the mycobacterium will enable us to determine how the redox balance is altered in response to signals and environments that mimic those encountered in the host.