The Transcription Factor ArcA Modulates Salmonella’s Metabolism in Response to Neutrophil Hypochlorous Acid-Mediated Stress

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.

The ABC-Type Efflux Pump MacAB Is Involved in Protection of Serratia marcescens against Aminoglycoside Antibiotics, Polymyxins, and Oxidative Stress

“…The analysis of the nucleotide sequence upstream of the macAB operon using Virtual Footprint promoter analysis v.3 ( 65 ) indicated the presence of putative binding sites for global regulators ArcA and OxyR (data not shown). Both transcription factors are known to positively regulate the expression of genes encoding components of the oxidative pathway ( 66 , 67 ). While the exact mechanism of MacAB regulation in S. marcescens is yet to be defined, our results clearly indicate that activation of the macAB promoter is peroxide-dependent.…”

Surviving Reactive Chlorine Stress: Responses of Gram-Negative Bacteria to Hypochlorous Acid

“…Other redox sensors primarily known to be involved in ROS resistance have also been described in HOCl response in Gram-negative bacteria. These include the two-component system aerobic respiration control (ArcAB) [ 82 , 143 , 144 ], SylA [ 145 ] and OhrR [ 134 ], which are members of the MarR family, PerR, which belongs to the Fur family [ 70 ], and ComR, controlled by the TetR family [ 70 ].…”

Two-component system ArcBA modulates cell motility and biofilm formation in Dickeya oryzae

“…Previous studies have unveiled that the Arc (aerobic respiratory control) TCS is a key regulatory system facilitating facultative anaerobic bacteria to sense and respond to various respiratory growth conditions and regulate their gene expression accordingly, such as Salmonella enterica serovar Typhimurium, E. coli, Haemophilus parasuis serova 13 clincal strain EP3, and S. enteritidis (Gao et al, 2007;Calderon et al, 2011;Cameron et al, 2013;Jiang et al, 2015;Ding et al, 2016;Basan et al, 2017;Chen and Goulian, 2018;Fernandez et al, 2018;Pardo-Este et al, 2019), as well as regulating virulence factor production, controlling metabolism, chemotaxis, motility and pathogenicity of avian pathogenic E. coli (Jiang et al, 2015), virulence of H. parasuis serovar 13 clinical strain EP3 (Ding et al, 2016), and swarming motility in Serratia marcescens FS14 (Zhang et al, 2018). Similarly, in this study, we demonstrated that ArcBA regulates the virulence traits, bacterial swimming and swarming motility, and gene expression of flagellar in D. oryzae (Figures 3A-C).…”