title: Cytochrome bd-Dependent Bioenergetics and Antinitrosative Defenses in Salmonella Pathogenesis.
abstract: In the course of an infection, Salmonella enterica occupies diverse anatomical sites with various concentrations of oxygen (O2) and nitric oxide (NO). These diatomic gases compete for binding to catalytic metal groups of quinol oxidases. Enterobacteriaceae express two evolutionarily distinct classes of quinol oxidases that differ in affinity for O2and NO as well as stoichiometry of H+translocated across the cytoplasmic membrane. The investigations presented here show that the dual function of bacterial cytochrome bd in bioenergetics and antinitrosative defense enhances Salmonella virulence. The high affinity of cytochrome bd for O2optimizes respiratory rates in hypoxic cultures, and thus, this quinol oxidase maximizes bacterial growth under O2-limiting conditions. Our investigations also indicate that cytochrome bd, rather than cytochrome bo, is an intrinsic component of the adaptive antinitrosative toolbox of Salmonella Accordingly, induction of cytochrome bd helps Salmonella grow and respire in the presence of inhibitory NO. The combined antinitrosative defenses of cytochrome bd and the flavohemoglobin Hmp account for a great part of the adaptations that help Salmonella recover from the antimicrobial activity of NO. Moreover, the antinitrosative defenses of cytochrome bd and flavohemoglobin Hmp synergize to promote Salmonella growth in systemic tissues. Collectively, our investigations indicate that cytochrome bd is a critical means by which Salmonella resists the nitrosative stress that is engendered in the innate response of mammalian hosts while it concomitantly allows for proper O2utilization in tissue hypoxia.
  
  
  
  It is becoming quite apparent that metabolism is critically important to the virulence potential of pathogenic microorganisms. Bacterial cells use a variety of terminal electron acceptors to power electron transport chains and metabolic processes. Of all the electron acceptors available to bacteria, utilization of O2yields the most energy while diversifying the type of substrates that a pathogen can use. Recent investigations have demonstrated important roles for bd-type quinol oxidases with high affinity for O2in bacterial pathogenesis. The investigations presented here have revealed that cytochrome bd potentiates virulence of a clinically relevant bacterial pathogen by fueling bioenergetics of prokaryotic cells while protecting the respiratory chain against NO toxicity. The adaptive antinitrosative defenses afforded by cytochrome bd synergize with other NO-detoxifying systems to preserve cellular bioenergetics, thereby promoting bacterial virulence in tissue hypoxia.
authors.affiliation: Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones-Carson
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Maroof
authors.initials: M
authors.lastname: Husain
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA andres.vazquez-torres@ucdenver.edu.|Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA.
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D000818:Animals; D003573:Cytochrome b Group / Q000378:metabolism*; D017937:Cytochrome d Group / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins; D004734:Energy Metabolism; D006801:Humans; D000860:Hypoxia; D007113:Immunity, Innate; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D019779:Salmonella enterica / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D013312:Stress, Physiological
chemical_list: D003573:Cytochrome b Group; D045222:Electron Transport Chain Complex Proteins; D009569:Nitric Oxide; D017937:Cytochrome d Group; D010088:Oxidoreductases; C020094:duroquinol oxidase; D010100:Oxygen