Investigating the role of yeie-induced sulfite response pathways in salmonella adaptation to neutrophil stress

The National Institute of Allergy and Infectious Diseases awarded the University of Wisconsin–Madison $124,386 on December 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of YeiE-induced sulfite response pathways in Salmonella adaptation to neutrophil stress.

The research defines the molecular mechanisms by which Salmonella enterica serotype Typhimurium, a leading foodborne pathogen, resists antimicrobial responses generated by neutrophils. The project tests the hypothesis that sulfite, a reactive sulfur species released by neutrophils during innate immune response, activates the transcriptional regulator YeiE in Salmonella, which in turn regulates a sulfite-responsive regulon that promotes bacterial resistance to neutrophil-mediated stress. Aim 1 integrates RNA-seq and ChIP-seq to define the YeiE regulon, identifying direct sulfite-responsive targets and testing sulfite-sensing requirements in vitro. Aim 2 investigates how sulfite influences neutrophil antimicrobial responses, including reactive oxygen species generation, phagocytosis, and neutrophil extracellular trap formation.

Performance occurs in Madison, Wisconsin, with a period of performance through August 31, 2029. This is a project grant, the standard assistance type for investigator-initiated research under the Allergy and Infectious Diseases Research program.

Abstract

Salmonella enterica serotype typhimurium is a leading cause of foodborne illness and has numerous strategies to resist host antimicrobial responses, including those generated by neutrophils. Neutrophils release a wide array of reactive compounds during the innate immune response, including sulfite, a reactive sulfur species that is cytotoxic and influences both host immune function and microbial physiology. Unlike eukaryotes that detoxify sulfite via sulfite oxidases or sulfite efflux transporters, the mechanisms by which bacteria tolerate sulfite stress remain unclear. Salmonella enterica is a genetically tractable, clinically relevant pathogen that naturally encounters neutrophil-derived stressors during infection, making IT an ideal model to study bacterial sulfite tolerance and host-pathogen interactions. Preliminary data in this proposal identify the lysr-type transcriptional regulator yeie as a key regulator of sulfite stress tolerance in salmonella. We have also defined a core set of yeie-dependent genes that are transcriptionally induced by sulfite. However, the molecular mechanisms linking sulfite sensing by yeie to downstream gene activation as well as the impact of sulfite on neutrophil function and salmonella survival remain poorly defined. This project will test the hypothesis that sulfite modulates neutrophil activity and activates yeie in salmonella, which in turn regulates a sulfite-responsive regulon that promotes bacterial resistance to neutrophil-mediated stress. Aim 1 will define the yeie regulon by integrating RNA-SEQ and chip-SEQ to identify direct sulfite-responsive targets and test the requirement for sulfite sensing in vitro. Aim 2 will investigate how sulfite influences neutrophil antimicrobial responses, such as reactive oxygen species generation, phagocytosis, and neutrophil extracellular trap formation, and determine the contribution of sulfite- regulated genes to salmonella survival during CO-culture with human neutrophils. Completion of this project will provide insight into how pathogens use stress-responsive transcriptional networks to thrive in inflamed tissues. Uncovering how salmonella survives sulfite stress could identify novel therapeutic targets to disrupt bacterial persistence during infection and reduce the public health burden of foodborne illnesses. This research will provide training in microbial pathogenesis, transcriptional regulation, and immunology in a highly collaborative and rigorous environment for physician-scientist development. Together, the research and training plan are designed to advance technical and clinical skills in translational microbiology and strengthen scientific communication, key areas of growth that will support progression toward an independent physician-scientist career.