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Title: The Complexities of Nitric Oxide Metabolism in Salmonella enterica serovar Typhimurium
Author: Gilberthorpe, Nicola J.
ISNI:       0000 0001 3498 6742
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2008
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S. typhimurium is able to survive and proliferate within macrophage cells and therefore possesses an array of defence mechanisms that allow it to resist antimicrobial stresses such as harsh nitrosative, oxidative and pH conditions. The relationship between S. typ!Iimurium and nitric oxide (NO) wa~ investigated. The resistance mechanisms that S. typhimurill11l employs to avoid nitrosative stress and the ability ofS. typ!Iimuriu11l to produce NO under certain conditions were examined. The regulation of the gene encoding flavohaemoglobin (!Imp) was studied in detail and NsrR was clearly demonstrated to have a role in the regulation of hmp in S. typ!Iimllriwn. Several other genes (ygbA, ytfE, hep, her) were also identified as being repressed by NsrR in non-nitrosating conditions. Construction and use of an nsrR lllnp double mutant demonstrated that an NsrR regulated gene(s) has the capacity to protect aerobic respiration from the inhibitory effects of NO. The requirement of functional Hmp intracellularly was also assessed; !Inlp mutants were shown to be attenuated only in IFN-r-activated macrophages, where the level ofNO produced by the macrophages was enhanced. Mutants in nsrR were also attenuated in IFN-r-activated macrophages suggesting that over-expression of !Imp is detrimental to the cells, . presumably due to production of O2- by high levels of Hmp. This demonstrates the importance of regulatory systems governing the expression of !Imp. Mutants in the iron responsive regulator, Fur, were attenuated in their ability to survive and proliferate in both nonstimulated and IFN-r-activated 1774.2 macrophages and it is suggested that these mutants are hyper-sensitive to a stress other than nitrosative, most probably oxidative stress. The ability of S, typltimurium to produce NO was investigated. The N03reductase (NarGHI) was identified as having the ability to produce NO from N02- in anaerobic conditions, in the absence of its preferred substrate, N03.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available