title: The NorR regulon is critical for Vibrio cholerae resistance to nitric oxide and sustained colonization of the intestines.
abstract: Vibrio cholerae, the cause of an often fatal infectious diarrhea, remains a large global public health threat. Little is known about the challenges V. cholerae encounters during colonization of the intestines, which genes are important for overcoming these challenges, and how these genes are regulated. In this study, we examined the V. cholerae response to nitric oxide (NO), an antibacterial molecule derived during infection from various sources, including host inducible NO synthase (iNOS). We demonstrate that the regulatory protein NorR regulates the expression of NO detoxification genes hmpA and nnrS, and that all three are critical for resisting low levels of NO stress under microaerobic conditions in vitro. We also show that prxA, a gene previously thought to be important for NO detoxification, plays no role in NO resistance under microaerobic conditions and is upregulated by H(2)O(2), not NO. Furthermore, in an adult mouse model of prolonged colonization, hmpA and norR were important for the resistance of both iNOS- and non-iNOS-derived stresses. Our data demonstrate that NO detoxification systems play a critical role in the survival of V. cholerae under microaerobic conditions resembling those of an infectious setting and during colonization of the intestines over time periods similar to that of an actual V. cholerae infection.
  
  
  OBJECTIVE
  Little is known about what environmental stresses Vibrio cholerae, the etiologic agent of cholera, encounters during infection, and even less is known about how V. cholerae senses and counters these stresses. Most prior studies of V. cholerae infection relied on the 24-h infant mouse model, which does not allow the analysis of survival over time periods comparable to that of an actual V. cholerae infection. In this study, we used a sustained mouse colonization model to identify nitric oxide resistance as a function critical for the survival of V. cholerae in the intestines and further identified the genes responsible for sensing and detoxifying this stress.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hay
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Desland
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Zengtao
authors.initials: Z
authors.lastname: Zhong
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000633:toxicity*; D018085:Regulon; D013312:Stress, Physiological; D014734:Vibrio cholerae / Q000235:genetics / Q000472:pathogenicity*
chemical_list: D001426:Bacterial Proteins; D009569:Nitric Oxide