Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis

Hydrogen sulfide (H₂S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived H₂S in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the H₂S-producing enzyme cystathionine β-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that H₂S stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that H₂S reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to H₂S regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived H₂S to promote growth and disease, and suggest that host-directed therapies targeting H₂S production may be potentially useful for the management of tuberculosis and other microbial infections.