Abstract
Salmonella Typhimurium, a bacterial pathogen with high metabolic plasticity, can adapt to different environmental conditions; these traits enhance its virulence by enabling bacterial survival. Neutrophils play important roles in the innate immune response, including the production of microbicidal reactive oxygen species (ROS). In addition, the myeloperoxidase in neutrophils catalyzes the formation of hypochlorous acid (HOCl), a highly toxic molecule that reacts with essential biomolecules, causing oxidative damage including lipid peroxidation and protein carbonylation. The bacterial response regulator ArcA regulates adaptive responses to oxygen levels and influences the survival of Salmonella inside phagocytic cells. Here, we demonstrate by whole transcriptomic analyses that ArcA regulates genes related to various metabolic pathways, enabling bacterial survival during HOCl-stress in vitro. Also, inside neutrophils, ArcA controls the transcription of several metabolic pathways by downregulating the expression of genes related to fatty acid degradation, lysine degradation, and arginine, proline, pyruvate, and propanoate metabolism. ArcA also upregulates genes encoding components of the oxidative pathway. These results underscore the importance of ArcA in ATP generation inside the neutrophil phagosome and its participation in bacterial metabolic adaptations during HOCl stress.
Highlights
IntroductionTo its infection cycle, this bacterium can survive the microbicidal action of immune cells, including neutrophils (Ibarra and Steele-Mortimer, 2009; Ruby et al, 2012; Behnsen et al, 2015)
To understand the role of ArcA during hypochlorous acid (HOCl)-related stress in vitro under conditions that could mimic those found in neutrophils, we sought to perform a transcriptomic analysis of the parental and arcA mutant strains
The growth rates of- arcA and the parental strain under this condition were similar, and the mutant could recover after the addition of NaOCl (Figure 1B)
Summary
To its infection cycle, this bacterium can survive the microbicidal action of immune cells, including neutrophils (Ibarra and Steele-Mortimer, 2009; Ruby et al, 2012; Behnsen et al, 2015). Salmonella promotes its own internalization to the host via several effector proteins associated with Salmonella Pathogenicity Island 1 (SPI-1), namely: SipA, SipC, and SptP (LaRock et al, 2015). The bacterium encounters the oxidative burst, a process in which oxygen is reduced to form superoxide radicals and other toxic reactive oxygen species (ROS). Neutrophils possess two enzymes at play: NADPH oxidase, which initiates the production of O2−, and myeloperoxidase (MPO), which produces hypochlorous acid (HOCl) (Winterbourn and Kettle, 2013)
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