Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis

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. Highresolution 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.

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

“…Although cytochrome bd oxidase does not pump protons, it still enables aerobic metabolism and robust growth. This respiratory switch in response to H 2 S may well occur in several other bacterial pathogens, including Acinetobacter baumannii (20) and Mycobacterium tuberculosis; in the latter case, low levels of H 2 S enhance the respiration, energy production, and survival of M. tuberculosis in infected mice (25). Further studies are required to establish the generality of this adaptive response across a wider range of organisms.…”

“…antibiotic and oxidative stress (22,24,25,99). In infected macrophages and in mice, Helicobacter pylori was found to induce the expression of the host transsulfuration pathway enzyme CSE ( Fig.…”

“…To understand the role of H 2 S and RSS in signaling at the host-pathogen interface, tools must be available that allow for the generation, detection, and quantification of these species in vivo. The type and number of molecular probes used for the generation of H 2 S and RSS have substantially increased over the past several years, and they are now being used in bacteria to provide critical insights into H 2 S signaling in these organisms (22,25,26). Fluorescence-based probes provide rapid and sensitive detection of H 2 S or sulfane sulfur with several options now commercially available.…”

“…In the infected host, H 2 S and RSS are derived from host cell metabolism, from commensal bacteria in polymicrobial communities, or from the pathogen itself. Recent studies that build on prior work (21) suggest that bacterial H 2 S biogenesis may well be a clinically important adaptive response during infections (22)(23)(24)(25)(26).…”

l-Cysteine-mediated modulation of copper trafficking in prostate cancer cells: an in vitro and in vivo investigation with 64Cu and 64Cu-PET

“…Apart from contributing to glutathione synthesis, L-cysteine can undergo numerous intracellular catabolic pathways, such as generation of taurine, pyruvate or hydrogen sulfide. 72 Hydrogen sulfide can trap 64 Cu at very low levels 73 or regulate copper export systems in Mycobacterium tuberculosis 74 and in human neuroblastoma cells. 75 S-Adenosylhomocysteine hydrolase, one of the key enzymes in the metabolism of thiol-containing amino acids, was found to bind appreciable amounts of copper in mouse livers 76 and its expression is regulated by copper availability in mice.…”