The Journal of Experimental Medicine
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/227/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 227-236

Original Article

Antimicrobial Actions of the Nadph Phagocyte Oxidase and Inducible Nitric Oxide Synthase in Experimental Salmonellosis. I. Effects on Microbial Killing by Activated Peritoneal Macrophages in Vitro

Andrés Vazquez-Torresa,b,c, Jessica Jones-Carsona,b,c, Pietro Mastroenid, Harry Ischiropoulose, and Ferric C. Fanga,b,c

a Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
b Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262
c Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262
d Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, United Kingdom
e Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
Departments of Medicine, Pathology, and Microbiology, University of Colorado Health Sciences Center (B168), 4200 E. 9th Ave., Denver, CO 80262.303-315-8681303-315-4857

ferric.fang{at}uchsc.edu

The contribution of the NADPH phagocyte oxidase (phox) and inducible nitric oxide (NO) synthase (iNOS) to the antimicrobial activity of macrophages for Salmonella typhimurium was studied by using peritoneal phagocytes from C57BL/6, congenic gp91phox–/–, iNOS–/–, and doubly immunodeficient phox–/–iNOS–/– mice. The respiratory burst and NO radical (NO·) made distinct contributions to the anti-Salmonella activity of macrophages. NADPH oxidase–dependent killing is confined to the first few hours after phagocytosis, whereas iNOS contributes to both early and late phases of antibacterial activity. NO-derived species initially synergize with oxyradicals to kill S. typhimurium, and subsequently exert prolonged oxidase-independent bacteriostatic effects. Biochemical analyses show that early killing of Salmonella by macrophages coincides with an oxidative chemistry characterized by superoxide anion (O2·–), hydrogen peroxide (H2O2), and peroxynitrite (ONOO–) production. However, immunofluorescence microscopy and killing assays using the scavenger uric acid suggest that peroxynitrite is not responsible for macrophage killing of wild-type S. typhimurium. Rapid oxidative bacterial killing is followed by a sustained period of nitrosative chemistry that limits bacterial growth. Interferon {gamma} appears to augment antibacterial activity predominantly by enhancing NO· production, although a small iNOS-independent effect was also observed. These findings demonstrate that macrophages kill Salmonella in a dynamic process that changes over time and requires the generation of both reactive oxidative and nitrosative species.

Key Words: phagocyte • Salmonella • innate immunity • nitrosative • oxidative

Abbreviations used in this paper: iNOS, inducible nitric oxide synthase; NO, nitric oxide; NOS, nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species.

© 2000 The Rockefeller University Press


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