title: Nitric oxide antagonizes the acid tolerance response that protects Salmonella against innate gastric defenses.
abstract: BACKGROUND
  Reactive nitrogen species (RNS) derived from dietary and salivary inorganic nitrogen oxides foment innate host defenses associated with the acidity of the stomach. The mechanisms by which these reactive species exert antimicrobial activity in the gastric lumen are, however, poorly understood.
  
  
  RESULTS
  The genetically tractable acid tolerance response (ATR) that enables enteropathogens to survive harsh acidity was screened for signaling pathways responsive to RNS. The nitric oxide (NO) donor spermine NONOate derepressed the Fur regulon that controls secondary lines of resistance against organic acids. Despite inducing a Fur-mediated adaptive response, acidified RNS largely repressed oral virulence as demonstrated by the fact that Salmonella bacteria exposed to NO donors during mildly acidic conditions were shed in low amounts in feces and exhibited ameliorated oral virulence. NO prevented Salmonella from mounting a de novo ATR, but was unable to suppress an already functional protective response, suggesting that RNS target regulatory cascades but not their effectors. Transcriptional and translational analyses revealed that the PhoPQ signaling cascade is a critical ATR target of NO in rapidly growing Salmonella. Inhibition of PhoPQ signaling appears to contribute to most of the NO-mediated abrogation of the ATR in log phase bacteria, because the augmented acid sensitivity of phoQ-deficient Salmonella was not further enhanced after RNS treatment.
  
  
  CONCLUSIONS
  Since PhoPQ-regulated acid resistance is widespread in enteric pathogens, the RNS-mediated inhibition of the Salmonella ATR described herein may represent a common component of innate host defenses.
authors: Department of Microbiology, University of Colorado Health Sciences Center, Aurora, Colorado, United States of America.
authors: Travis J
authors: TJ
authors: Bourret
authors: Steffen
authors: S
authors: Porwollik
authors: Michael
authors: M
authors: McClelland
authors: Rui
authors: R
authors: Zhao
authors: Todd
authors: T
authors: Greco
authors: Harry
authors: H
authors: Ischiropoulos
authors: Andrés
authors: A
authors: Vázquez-Torres
mesh_terms: D000143:Acids; D000222:Adaptation, Physiological; D000818:Animals; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D019779:Salmonella enterica / Q000472:pathogenicity / Q000502:physiology*; D013270:Stomach / Q000276:immunology* / Q000382:microbiology; D014774:Virulence
chemical_list: D000143:Acids; D020030:Nitric Oxide Donors; D009569:Nitric Oxide