The Journal of Experimental Medicine
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/237/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 237-248


Original Article

Antimicrobial Actions of the NADPH Phagocyte Oxidase and Inducible Nitric Oxide Synthase in Experimental Salmonellosis. II. Effects on Microbial Proliferation and Host Survival In Vivo

Pietro Mastroenia,b, Andrés Vazquez-Torresc,d,e, Ferric C. Fangc,d,e, Yisheng Xuc,d,e, Shahid Khana, Carlos E. Hormaechea,f, and Gordon Douganb
a Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, United Kingdom
b Department of Biochemistry, Imperial College, London SW7 2AZ, United Kingdom
c Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
d Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262
e Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262
f Department of Microbiology and Immunology, The Medical School, University of Newcastle, Newcastle upon Tyne, NE2 4HH, United Kingdom

Correspondence to: Pietro Mastroeni, Centre for Veterinary Science, University of Cambridge, Madingley Road, Cambridge CB3 OES, UK. Tel:44-1223-339868 Fax:44-1223-337610 E-mail:pm274{at}cm.ac.uk.

The roles of the NADPH phagocyte oxidase (phox) and inducible nitric oxide synthase (iNOS) in host resistance to virulent Salmonella typhimurium were investigated in gp91phox-/-, iNOS-/-, and congenic wild-type mice. Although both gp91phox-/- and iNOS-/- mice demonstrated increased susceptibility to infection with S. typhimurium compared with wild-type mice, the kinetics of bacterial replication were dramatically different in the gp91phox-/- and iNOS-/- mouse strains. Greater bacterial numbers were present in the spleens and livers of gp91phox-/- mice compared with C57BL/6 controls as early as day 1 of infection, and all of the gp91phox-/- mice succumbed to infection within 5 d. In contrast, an increased bacterial burden was detected within reticuloendothelial organs of iNOS-/- mice only beyond the first week of infection. Influx of inflammatory CD11b+ cells, granuloma formation, and serum interferon {gamma} levels were unimpaired in iNOS-/- mice, but the iNOS-deficient granulomas were unable to limit bacterial replication. The NADPH phagocye oxidase and iNOS are both required for host resistance to wild-type Salmonella, but appear to operate principally at different stages of infection.

Key Words: Salmonella, virulence, innate immunity, oxidative, nitrosative


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