Abstract
The microbial adaptations to the respiratory burst remain poorly understood, and establishing how the NADPH oxidase (NOX2) kills microbes has proven elusive. Here we demonstrate that NOX2 collapses the ΔpH of intracellular Salmonella Typhimurium. The depolarization experienced by Salmonella undergoing oxidative stress impairs folding of periplasmic proteins. Depolarization in respiring Salmonella mediates intense bactericidal activity of reactive oxygen species (ROS). Salmonella adapts to the challenges oxidative stress imposes on membrane bioenergetics by shifting redox balance to glycolysis and fermentation, thereby diminishing electron flow through the membrane, meeting energetic requirements and anaplerotically generating tricarboxylic acid intermediates. By diverting electrons away from the respiratory chain, glycolysis also enables thiol/disulfide exchange-mediated folding of bacterial cell envelope proteins during periods of oxidative stress. Thus, primordial metabolic pathways, already present in bacteria before aerobic respiration evolved, offer a solution to the stress ROS exert on molecular targets at the bacterial cell envelope.
Highlights
The microbial adaptations to the respiratory burst remain poorly understood, and establishing how the NADPH oxidase (NOX2) kills microbes has proven elusive
Fitness analysis confirmed the importance of divalent cation transporters corA and mgtB, glutathione synthase gshB, and the two-component regulatory system phoP-phoQ in the resistance of Salmonella to oxidative stress (Supplementary Data 1 and 2)
The production of reactive oxygen species (ROS) by NOX2 is essential in the innate host response against a variety of bacterial and fungal pathogens
Summary
The microbial adaptations to the respiratory burst remain poorly understood, and establishing how the NADPH oxidase (NOX2) kills microbes has proven elusive. Depolarization in respiring Salmonella mediates intense bactericidal activity of reactive oxygen species (ROS). Salmonella adapts to the challenges oxidative stress imposes on membrane bioenergetics by shifting redox balance to glycolysis and fermentation, thereby diminishing electron flow through the membrane, meeting energetic requirements and anaplerotically generating tricarboxylic acid intermediates. By diverting electrons away from the respiratory chain, glycolysis enables thiol/disulfide exchange-mediated folding of bacterial cell envelope proteins during periods of oxidative stress. ROS generated through the enzymatic activity of the phagocyte NADPH oxidase (NOX2) are among the most potent host defenses pathogenic microorganisms face during infection. It is widely accepted that reactive oxygen species generated in the respiratory burst damage DNA via Fenton-mediated chemistry and oxidize protein cysteine residues and metal cofactors in regulatory and metabolic proteins[6,7,8]. Salmonella adapts to the challenge oxidative stress imposes to membrane energetics by shifting redox balance from oxidative phosphorylation to glycolysis
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