# Molecular determinants of oxidative stress in Salmonella pathogenesis > **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $505,126 ## Abstract ABSTRACT: Almost two billion people worldwide become ill with diarrhea annually, and ~700,000 die. Nontyphoidal Salmonella, such as Typhimurium, cause roughly 180 million diarrheal illnesses and 300,000 of all diarrheal disease-associated deaths. Very young and very old people, as well as immunosuppressed individuals coinfected with HIV or plasmodium, are particularly at risk of suffering life-threatening, systemic nontyphoidal Salmonella infections. During infection, phagocytic cells bombard Salmonella with highly toxic reactive oxygen species produced in the respiratory burst of the protein complex NOX2. The metabolic adaptations that promote growth of Salmonella in macrophages are vital yet largely neglected facets in the pathogenesis of this intracellular bacterium. In the current grant period, we made a series of crucial new observations regarding the hitherto poorly understood terminal electron acceptors used by intracellular Salmonella to resist NOX2 killing. (a) Salmonella exploit anaerobic respiration in order to avoid metabolic pathways particularly sensitive to reactive oxygen species synthesized by NOX2. (b) The O2-consuming activity of phagocytic cells activates Salmonella anaerobic programs in mice, macrophages and hypoxic culture conditions that recapitulate microabscesses developing during Salmonella systemic infections. (c) Anaerobic respiration associated with dmsABC gene products is required for survival of Salmonella in phagocytes and mice. (d) We have identified methionine sulfoxide, a byproduct of NOX2 enzymatic activity in mice, as the relevant terminal electron acceptor utilize by dmsABC gene products. (e) Anaerobic respiration on methionine sulfoxide is associated with production of the antioxidant hydrogen sulfide (H2S) in anaerobic Salmonella undergoing oxidative stress. (f) Intracellular Salmonella also respires on the sulfur compound tetrathionate to avoid NOX2 killing in macrophages, while activating the expression of Salmonella virulence programs. Cumulatively, our data support the hypothesis that intracellular Salmonella has coopted the energetics and signaling pathways arising from a sulfur-centric anaerobic metabolism to counteract the damaging activity of NOX2 enzymatic complexes in macrophages. Aim 1 will investigate the contribution of DmsA-dependent anaerobic respiration to the resistance of intracellular Salmonella to NOX2. Aim 2 will evaluate the degree to which hydrogen sulfide aids the defense of intracellular Salmonella against oxidative stress. Aim 3 will identify the mechanisms through which tetrathionate respiration fosters the antioxidant defenses of intracellular Salmonella. The knowledge generated in the course of these investigations will not only illuminate key aspects of Salmonella pathogenesis but will also identify key terminal electron acceptors utilized by intracellular Salmonella to establish a stronghold within professional macrophages. ## Key facts - **NIH application ID:** 10882502 - **Project number:** 2R01AI136520-06A1 - **Recipient organization:** UNIVERSITY OF COLORADO DENVER - **Principal Investigator:** Andres Vazquez-Torres - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $505,126 - **Award type:** 2 - **Project period:** 2024-08-16 → 2028-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10882502 ## Citation > US National Institutes of Health, RePORTER application 10882502, Molecular determinants of oxidative stress in Salmonella pathogenesis (2R01AI136520-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10882502. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*