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

doi:10.1084/jem.192.2.227

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-Torres^a,b,c, Jessica Jones-Carson^a,b,c, Pietro Mastroeni^d, Harry Ischiropoulos^e, and Ferric C. Fang^a,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

Correspondence to: Ferric C. Fang, Departments of Medicine, Pathology, and Microbiology, University of Colorado Health Sciences Center (B168), 4200 E. 9th Ave., Denver, CO 80262. Tel:303-315-4857 Fax:303-315-8681 E-mail:ferric.fang{at}uchsc.edu.

The contribution of the NADPH phagocyte oxidase (phox) and induciblenitric oxide (NO) synthase (iNOS) to the antimicrobial activityof macrophages for Salmonella typhimurium was studied by usingperitoneal phagocytes from C57BL/6, congenic gp91phox^-/-, iNOS^-/-,and doubly immunodeficient phox^-/-iNOS^-/- mice. The respiratoryburst and NO radical (NO·) made distinct contributionsto the anti-Salmonella activity of macrophages. NADPH oxidase–dependentkilling is confined to the first few hours after phagocytosis,whereas iNOS contributes to both early and late phases of antibacterialactivity. NO-derived species initially synergize with oxyradicalsto kill S. typhimurium, and subsequently exert prolonged oxidase-independentbacteriostatic effects. Biochemical analyses show that earlykilling of Salmonella by macrophages coincides with an oxidativechemistry characterized by superoxide anion (O₂·^-), hydrogenperoxide (H₂O₂), and peroxynitrite (ONOO^-) production. However,immunofluorescence microscopy and killing assays using the scavengeruric acid suggest that peroxynitrite is not responsible formacrophage killing of wild-type S. typhimurium. Rapid oxidativebacterial killing is followed by a sustained period of nitrosativechemistry that limits bacterial growth. Interferon ${gamma}$ appearsto augment antibacterial activity predominantly by enhancingNO· production, although a small iNOS-independent effectwas also observed. These findings demonstrate that macrophageskill Salmonella in a dynamic process that changes over timeand requires the generation of both reactive oxidative and nitrosativespecies.

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

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