YeiE regulates YeiH to implement sulfite stress resistance in <i>Salmonella enterica</i> serotype Typhimurium

Sulfites are toxic, reactive sulfur species that are widespread in nature. Bacteria are exposed to sulfites during the metabolism of sulfur-containing amino acids, during respiration using sulfur-containing electron acceptors, in host environments, and as food preservatives. Despite the widespread distribution of sulfites, the mechanisms by which bacteria resist their toxic effects are poorly understood. Recent work showed that the LysR-type transcriptional regulator YeiE binds to sulfite to activate sulfite reduction gene expression. We show that YeiE is necessary for <i>Salmonella</i> fitness in a murine infection model. We demonstrate here that the mechanism of sulfite stress resistance is distinct from pathways of sulfur assimilation for cysteine biogenesis. YeiE is an autoregulator whose expression is enhanced by sulfite. YeiE is necessary for growth under sulfite stress because it regulates the poorly characterized adjacent gene, <i>yeiH</i>. A <i>yeiH</i> deletion mutant is more sensitive to the growth-inhibiting effects of sulfite than a <i>yeiE</i> deletion mutant, demonstrating YeiH is the primary driver of sulfite stress resistance <i>in vitro</i>. This work provides a fundamental advance in understanding the sulfite stress response in bacteria, with broad implications for food safety and host-pathogen interactions.IMPORTANCESulfites are common, toxic, reactive sulfur species that bacteria encounter during amino acid metabolism, respiration, host interactions, and exposure to food preservatives. Despite their widespread presence, how bacteria detoxify sulfites is not well understood. Recent studies reveal that the transcriptional regulator YeiE binds sulfite and activates genes involved in sulfite reduction. We demonstrate that YeiE is important for <i>Salmonella</i> survival in infection and for growth during sulfite stress <i>in vitro</i>. YeiE controls the adjacent, poorly characterized inner membrane gene <i>yeiH</i>. YeiH is a key factor in sulfite stress resistance. Since YeiH is highly conserved among bacteria, this work has broad significance for understanding how bacteria resist reactive sulfur species during host-pathogen interactions and in the food supply.