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Infection and Immunity, August 2002, p. 4399-4405, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4399-4405.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Flavohemoglobin Hmp Protects Salmonella enterica Serovar Typhimurium from Nitric Oxide-Related Killing by Human Macrophages

Tânia M. Stevanin,1,2 Robert K. Poole,1 Eric A. G. Demoncheaux,3 and Robert C. Read2*

Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield S10 2TN,1 Division of Genomic Medicine,2 Division of Clinical Sciences (South), Royal Hallamshire Hospital, University of Sheffield Medical School, Sheffield S10 2RX, United Kingdom3

Received 23 January 2002/ Returned for modification 2 April 2002/ Accepted 6 May 2002

Survival of macrophage microbicidal activity is a prerequisite for invasive disease caused by the enteric pathogen Salmonella enterica serovar Typhimurium. Flavohemoglobins, such as those of Escherichia coli, Salmonella, and yeast, play vital roles in protection of these microorganisms in vitro from nitric oxide (NO) and nitrosative stress. A Salmonella hmp mutant defective in flavohemoglobin (Hmp) synthesis exhibits growth that is hypersensitive to nitrosating agents. We found that respiration of this mutant exhibited increased inhibition by NO, whereas wild-type cells pregrown with sodium nitroprusside or S-nitrosoglutathione showed enhanced tolerance of NO. Most significantly, hmp mutants internalized by primary human peripheral monocyte-derived macrophages survived phagocytosis relatively poorly compared with similarly bound and internalized wild-type cells. That the enhanced sensitivity to macrophage microbicidal activity is due primarily to the failure of Salmonella to detoxify NO was suggested by the ability of L-NG-monomethyl arginine—an inhibitor of NO synthase—to eliminate the difference in killing between wild-type and hmp mutant Salmonella cells. These observations suggest that Salmonella Hmp contributes to protection from NO-mediated inhibition by human macrophages.

* Corresponding author. Mailing address: Academic Unit of Infection and Immunity, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom. Phone: 44 114 271 3561. Fax: 44 114 273 9926. E-mail: r.c.read{at}shef.ac.uk.

Editor: A. D. O'Brien

Infection and Immunity, August 2002, p. 4399-4405, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4399-4405.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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