The Role of the ArcA Metabolic Regulator in Gram-Negative Bacteremia

Infections of the bloodstream are life-threatening and can result in sepsis. Gram-negative bacteria cause a significant portion of bloodstream infections, which is also referred to as bacteremia. The long-term goal of this work is to understand how such bacteria establish and maintain infection during bacteremia. Our research group has previously identified the transcription factor ArcA, which promotes fermentation in bacteria, as a likely contributor to the growth and survival of bacteria in this environment. Here, I study ArcA in the Gram-negative species Citrobacter freundii, Klebsiella pneumoniae, and Serratia marcescens and demonstrate that this transcription factor which represses aerobic respiration is necessary when cells encounter decreased oxygen levels, iron limitation, and perturbations to the membrane. Based on the requirement of ArcA, I hypothesized pathways underpinning aerobic respiration would be dispensable for these species during bacteremia but necessary for Escherichia coli for which ArcA is not a bacteremia fitness factor. Expendability of ubiquinone synthesis, a key pathway of aerobic respiration, did not correlate with essentiality of ArcA during bacteremia, suggesting that ArcA function does not necessitate absence of aerobic respiration and further species-specific metabolic activity needs to be explored. My findings overall aid in determining how bacteria sense their environment, utilize nutrients, and generate energy while countering the host immune system. This information is critical for understanding how ArcA promotes fitness during pathogenesis.