The Role of Host-Generated H₂S in Microbial Pathogenesis: New Perspectives on Tuberculosis

For centuries, hydrogen sulfide (H₂S) was considered primarily as a poisonous gas and environmental hazard. However, with the discovery of prokaryotic and eukaryotic enzymes for H₂S production, breakdown, and utilization, H₂S has emerged as an important signaling molecule in a wide range of physiological and pathological processes. Hence, H₂S is considered a gasotransmitter along with nitric oxide (•NO) and carbon monoxide (CO). Surprisingly, despite having overlapping functions with •NO and CO, the role of host H₂S in microbial pathogenesis is understudied and represents a gap in our knowledge. Given the numerous reports that followed the discovery of •NO and CO and their respective roles in microbial pathogenesis, we anticipate a rapid increase in studies that further define the importance of H₂S in microbial pathogenesis, which may lead to new virulence paradigms. Therefore, this review provides an overview of sulfide chemistry, enzymatic production of H₂S, and the importance of H₂S in metabolism and immunity in response to microbial pathogens. We then describe our current understanding of the role of host-derived H₂S in tuberculosis (TB) disease, including its influences on host immunity and bioenergetics, and on Mycobacterium tuberculosis (Mtb) growth and survival. Finally, this review discusses the utility of H₂S-donor compounds, inhibitors of H₂S-producing enzymes, and their potential clinical significance.