The sulfur assimilation pathway mitigates redox stress from acidic pH in <i>Salmonella</i> Typhi H58

In this study, we examined the clinically relevant, multi-drug resistant <i>Salmonella</i> Typhi strain H58, which is rapidly disseminating across Southeast Asia, Africa, and Oceania. It has heretofore been uncharacterized in terms of its gene regulation. Using human THP-1 macrophages, we discovered that S. Typhi strongly activates the sulfur utilization pathway in response to acid stress encountered in the vacuole once Typhi is inside host cells. Our novel findings were that <i>S.</i> Typhi experiences substantially higher redox stress compared with Typhimurium, and it requires the sulfur utilization pathway to mitigate this stress. This pathway is not upregulated in Typhimurium and represents a divergence in the response of these two serovars. We emphasize that <i>S.</i> Typhimurium is not a reasonable model for understanding H58, a serovar that is seriously impacting human health.