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Bacterial nitric oxide detoxification prevents host cell S-nitrosothiol formation: a novel mechanism of bacterial pathogenesis

Jay R. Laver^*,1, Tânia M. Stevanin^*, Sarah L. Messenger^*, Amy Dehn Lunn^*, Margaret E. Lee^*, James W. B. Moir, Robert K. Poole and Robert C. Read^*

^* Department of Infection and Immunity and

Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK; and

Department of Biology, University of York, Heslington, UK

¹ Correspondence: Department of Infection and Immunity, Medical School, Royal Hallamshire Hospital, Beech Hill Rd., Sheffield, South Yorkshire, UK. E-mail: j.r.laver{at}sheffield.ac.uk

S-nitrosylation is an important mediator of multiple nitric oxide-dependent biological processes, including eukaryotic cellular events such as macrophage apoptosis and proinflammatory signaling. Many pathogenic bacteria possess NO detoxification mechanisms, such as the nitric oxide reductase (NorB) of Neisseria meningitidis and the flavohemoglobins (Hmp) of Salmonella enterica and Escherichia coli, which serve to protect the microorganism from nitrosative stress within the intracellular environment. In this study, we demonstrate that expression of meningococcal NorB increases the rate at which low-molecular-weight S-nitrosothiol (SNO) decomposes in vitro. To determine whether this effect occurs in cells during infection by bacteria, we induced SNO formation in murine macrophages by activation with lipopolysaccharide and -interferon and observed a reduced abundance of SNO during coincubation with N. meningitidis, S. enterica, or E. coli. In each case, this effect was shown to be dependent on bacterial NO detoxification genes, which act to prevent SNO formation through the removal of NO. This may represent a novel mechanism of host cell injury by bacteria.—Laver, J. R., Stevanin, T. M., Messenger, S. L., Dehn Lunn, A., Lee, M. E., Moir, J. W. B., Poole, R. K., Read, R. C. Bacterial nitric oxide detoxification prevents host cell S-nitrosothiol formation: a novel mechanism of bacterial pathogenesis.

Key Words: S-nitrosylation • infection • macrophage • nitrosative stress