The Journal of Experimental Medicine
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Published online 29 April 2002 doi:10.1084/jem.20011547
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© Rockefeller University Press, 0022-1007/2002/5/1155/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 9, May 6, 2002 1155-1166
Salmonella Pathogenicity Island 2 Mediates Protection of Intracellular Salmonella from Reactive Nitrogen Intermediates

Dipshikha Chakravortty, Imke Hansen-Wester and Michael Hensel

Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany

Address correspondence to Dr. Michael Hensel, Institut für Klinische Mikrobiologie, Immunologie und Hygiene, FAU Erlangen-Nürnberg, D-91054 Erlangen, Germany. Phone: 49-9131-85-23640; Fax: 49-9131-85-22531; E-mail: hensel{at}mikrobio.med.uni-erlangen.de

Salmonella typhimurium causes an invasive disease in mice that has similarities to human typhoid. A type III protein secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is essential for virulence in mice, as well as survival and multiplication within macrophages. Reactive nitrogen intermediates (RNI) synthesized by inducible nitric oxide synthase (iNOS) are involved in the control of intracellular pathogens, including S. typhimurium. We studied the effect of Salmonella infection on iNOS activity in macrophages. Immunofluorescence microscopy demonstrated efficient colocalization of iNOS with bacteria deficient in SPI2 but not wild-type Salmonella, and suggests that the SPI2 system interferes with the localization of iNOS and Salmonella. Furthermore, localization of nitrotyrosine residues in the proximity was observed for SPI2 mutant strains but not wild-type Salmonella, indicating that peroxynitrite, a potent antimicrobial compound, is excluded from Salmonella-containing vacuoles by action of SPI2. Altered colocalization of iNOS with intracellular Salmonella required the function of the SPI2-encoded type III secretion system, but not of an individual "Salmonella translocated effector." Inhibition of iNOS increased intracellular proliferation of SPI2 mutant bacteria and, to a lesser extent, of wild-type Salmonella. The defect in systemic infection of a SPI2 mutant strain was partially restored in iNOS-/- mice. In addition to various strategies to detoxify RNI or repair damage due to RNI, avoidance of colocalization with RNI is important in adaptation of a pathogen to an intracellular life style.

Key Words: Salmonella typhimurium • SPI2 • iNOS • peroxynitrite • innate immunity


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