Role of S-nitrosothiol depletion in meningococcal sepsis and potential for novel therapy
Dr David Dockrell, Dr Jay Laver, Prof Rob Read
- Start Date:
19 June 2009
University of Sheffield, Sheffield, UK
Meningococcal sepsis is associated with severe and rapid physiological disruption and microcirculatory failure that is often non-refractory despite intensive resuscitation. Nitric oxide (NO) is a host molecule critical for cell signalling and homeostasis, mediated by the post-translational modification of cell proteins by S-nitrosylation. Neisseria meningitidis (Nm) has NO detoxification systems that enable respiration in microaerophilic environments and protect it from nitrosative stress. We have shown in our preliminary work that Nm infection of cells is associated with depletion of NO and of S-nitrosothiols (SNO), and that this effect is dependent on the bacterial nitric oxide reductase encoded by norB. This phenomenon is predicted to result in major cellular dysfunction. S-nitrosothiols are stable structures with long half-lives and long generation times, so we postulate that SNO depletion may be one mechanism that underlies the physiological dysfunction in meningococcal disease.
Drugs already exist that could be adapted to replenish SNO in the tissues of patients. Therefore, in this study we will confirm that SNO depletion in host cells during infection by Nm disrupts cardinal and measurable SNO-dependent cell activities namely: (i) GAPDH nuclear translocation, (ii) caspase activation and (iii) NfκB nuclear translocation, and that these effects also occur in tissues in a model of Nm bacteraemia. The potential utility of exogenous SNO donation using S-nitrosoglutathione (GSNO) to reverse the physiological effects of SNO depletion at both the cellular and whole animal level will then be tested.