Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis
Vikram Saini, Krishna C. Chinta, Vineel P. Reddy, Joel N. Glasgow, Asaf Stein, Dirk A. Lamprecht, Md. Aejazur Rahman, Jared S. Mackenzie, Barry Truebody, John Adamson, Tafara T. R. Kunota, Shannon M. Bailey, Douglas R. Moellering, Jack R. Lancaster, Adrie J. C. Steyn
Abstract
Abstract Hydrogen sulfide (H 2 S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and • NO. However, the importance of host-derived H 2 S in microbial pathogenesis is unknown. Here we show that Mtb -infected mice deficient in the H 2 S-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 H 2 S stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that H 2 S reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to H 2 S regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived H 2 S to promote growth and disease, and suggest that host-directed therapies targeting H 2 S production may be potentially useful for the management of tuberculosis and other microbial infections.