Regulation and Function of the Neisserial Denitrification Pathway: Life with Limited Oxygen
Virginia L. Clark, Vincent M. Isabella, Kenneth Barth and Tim W. Overton
from: Neisseria: Molecular Mechanisms of Pathogenesis (Edited by: Caroline Genco and Lee Wetzler). Caister Academic Press, U.K. (2010)
Neisseria gonorrhoeae and N. meningitidis can grow anaerobically and/or microaerobically by anaerobic respiration, using the central two enzymes of the denitrification pathway. Nitrite reductase (AniA) converts nitrite to nitric oxide (NO), which is then reduced to nitrous oxide by nitric oxide reductase (NorB). The regulation of expression of aniA and norB is complex, involving multiple transcriptional activators and/or repressors. Transcription of aniA only occurs when oxygen concentrations are low due to the absolute requirement for FNR, an oxygen-sensitive transcriptional activator. When nitrite is present, it is converted to nitric oxide by AniA, resulting in inactivation of the repressor, NsrR, and commensurate derepression and NarP-dependent activation. Expression of norB is controlled by three repressors, NsrR, Fur, and ArsR. Transcription of norB can occur aerobically if nitric oxide is present, by inactivation of NsrR. Fur and ArsR compete for overlapping binding sites; Fur + iron displaces ArsR, causing further derepression of norB. In addition to enabling growth under oxygen-limited conditions, the denitrification pathway may alter nitric oxide concentrations during infection, leading to changes in NF-κB activation and resulting in suppression of the immune response. When a long-half life NO donor is added to mimic host production of NO, gonococci reduce NO from a pro-inflammatory (> 1 μM) to an anti-inflammatory steady state concentration (100-200 nM). In the presence of nitrite, most strains produce a high steady state level of NO, while strains requiring arginine, hypoxanthine, and uracil (AHU) set a steady state level < 1 μM. In meningococci the presence of the denitrification pathway protects the bacterium against the toxic effects of reactive nitrogen species and also alters cytokine production profiles by host macrophages read more ...