Abstract
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.
Highlights
Hydrogen sulfide (H2S) is involved in numerous pathophysiological processes and shares overlapping functions with carbon monoxide (CO) and NO
Bacterial recovery from Mtbinfected Cbs+/− peritoneal macrophages was reduced compared to WT cells (Fig. 1e), which correlates with lower H2S levels in these cells as measured by an H2S-specific probe (Fig. 1f)
Our data show that H2S stimulates Mycobacterium tuberculosis (Mtb) respiration, predominately via cytochrome bd-type menaquinol oxidase (CytBD), and reprograms central metabolism leading to enhanced growth
Summary
Hydrogen sulfide (H2S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and NO. Highresolution 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. Despite having several overlapping functions with CO and NO8,12, a role for host-generated H2S in bacterial pathogenesis has not yet been described. We hypothesize that host-derived H2S plays a role in TB through modulation of Mtb respiration and bioenergetics. To test this hypothesis, we performed Mtb infection studies in CBS-deficient (Cbs+/−) mice, which have reduced H2S levels. We examined the role of CBS in inflammation, determined the total sulfide levels in infected mice, and examined how H2S modulates Mtb growth, gene expression, metabolism and respiration
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