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

Abstract

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 γ 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.

Genetic regulation of host responses to Salmonella infection in mice

“…124 This observation contrasts with the gp91 phox -deficient mice which are extremely susceptible to Salmonella Typhimurium early during the course of infection even with a very low inoculum. 124 It is clear from these studies that intracellular killing of Salmonella Typhimurium is dependent on both ROI and RNI systems; however these reactive intermediates appear to act at different stages of infection (NADPH oxidase being more critical early after infection and Nos2 later during infection). Double mutant mice (gp91 phoxÀ/À / Nos2 À/À ) exhibited spontaneous infections caused by organisms of the normal flora, resulting in the formation of large internal abscesses.…”

“…Mice deficient in gp91 phox were engineered as a model for CGD and found to be extremely susceptible to infection with Salmonella Typhimurium. 124,125 Early death of gp91 phox -deficient mice after Salmonella infection was associated with spleen and liver bacterial load exceeding by at least 3 log the wild-type controls. 124 Studies with Nos2-deficient mice support a dual role for NO during virulent Salmonella infection in vivo.…”

“…124,125 Early death of gp91 phox -deficient mice after Salmonella infection was associated with spleen and liver bacterial load exceeding by at least 3 log the wild-type controls. 124 Studies with Nos2-deficient mice support a dual role for NO during virulent Salmonella infection in vivo. Enhanced production of NO provides increased host defense against pathogens but also contributes to inflammation, tissue damage and even endotoxic shock.…”

“…Enhanced production of NO provides increased host defense against pathogens but also contributes to inflammation, tissue damage and even endotoxic shock. 124,126,127 Although Nos2 knockout mice are able to control the early replication of Salmonella in the RES organs, they are unable to suppress bacterial growth later during infection and eventually die. 124 This observation contrasts with the gp91 phox -deficient mice which are extremely susceptible to Salmonella Typhimurium early during the course of infection even with a very low inoculum.…”

“…124,126,127 Although Nos2 knockout mice are able to control the early replication of Salmonella in the RES organs, they are unable to suppress bacterial growth later during infection and eventually die. 124 This observation contrasts with the gp91 phox -deficient mice which are extremely susceptible to Salmonella Typhimurium early during the course of infection even with a very low inoculum. 124 It is clear from these studies that intracellular killing of Salmonella Typhimurium is dependent on both ROI and RNI systems; however these reactive intermediates appear to act at different stages of infection (NADPH oxidase being more critical early after infection and Nos2 later during infection).…”