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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.

Mastroeni P, Vazquez-Torres A, Fang FC, Xu Y, Khan S, Hormaeche CE, Dougan G - J. Exp. Med. (2000)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, United Kingdom. pm274@cm.ac.uk

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 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.

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(continues on facing page). Microscopic appearance of livers and spleens from gp91phox−/−, iNOS−/−, and congenic wild-type mice infected with S. typhimurium. C57BL/6, gp91phox−/−, and iNOS−/− were infected as described in the legend to Fig. 2. Hematoxylin and eosin–stained sections were prepared from spleens and livers harvested at time points thereafter. Microabscesses were seen in the livers of (A) gp91phox−/−, (B) iNOS−/−, and (C) wild-type animals on day 3. Granulomatous lesions were seen within the (D and E) spleens and (F and G) livers of (D and F) iNOS−/− and (E and G) wild-type C57BL/6 mice on day 8 (original magnification: ×200). The histopathology from days 11 and 14 closely resembled that observed on day 8. Necrotic lesions were detected in the (H and I) livers and (J and K) spleens of iNOS−/− mice on day 21. Approximate original magnifications: A–G, ×400; H, ×60; I, ×200; and J–K, ×400.
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Figure 4: (continues on facing page). Microscopic appearance of livers and spleens from gp91phox−/−, iNOS−/−, and congenic wild-type mice infected with S. typhimurium. C57BL/6, gp91phox−/−, and iNOS−/− were infected as described in the legend to Fig. 2. Hematoxylin and eosin–stained sections were prepared from spleens and livers harvested at time points thereafter. Microabscesses were seen in the livers of (A) gp91phox−/−, (B) iNOS−/−, and (C) wild-type animals on day 3. Granulomatous lesions were seen within the (D and E) spleens and (F and G) livers of (D and F) iNOS−/− and (E and G) wild-type C57BL/6 mice on day 8 (original magnification: ×200). The histopathology from days 11 and 14 closely resembled that observed on day 8. Necrotic lesions were detected in the (H and I) livers and (J and K) spleens of iNOS−/− mice on day 21. Approximate original magnifications: A–G, ×400; H, ×60; I, ×200; and J–K, ×400.

Mentions: Microscopic examination of livers of C57BL/6 and congenic gp91phox−/− and iNOS−/− mice revealed the early formation of microabscesses rich in polymorphonuclear neutrophils by day 3 of infection (Fig. 4aFig. bFig. c), with more extensive lesions noted in the gp91phox−/− animals. On days 8, 11, and 14, the focal lesions in the spleens and livers of the infected C57BL/6 and iNOS−/− mice consisted mainly of mononuclear cells and were surrounded by normal tissue. This evolution of the inflammatory response 1018 occurred similarly in both iNOS−/− mice (Fig. 4d and Fig. f) and C57BL/6 mice (Fig. 4e and Fig. g), showing no iNOS dependence on the formation of mononuclear cell–rich granulomas. In several iNOS−/− mice it was visually evident that the average size of focal granulomas was larger than in congenic wild-type control mice. On day 21 of infection, granulomatous lesions present in the livers and spleens of iNOS−/− mice in the C57BL/6 background showed a variable degree of central necrosis (Fig. 4hFig. iFig. jFig. k); macroscopically visible abscesses were present in the livers and occasionally in the spleens. The histological picture in organs of wild-type 129Sv and congenic iNOS−/− mice infected with S. typhimurium C5 was similar to that described in the C57BL/6 strain background, except for the absence of central necrosis in the hepatic and splenic lesions.


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.

Mastroeni P, Vazquez-Torres A, Fang FC, Xu Y, Khan S, Hormaeche CE, Dougan G - J. Exp. Med. (2000)

(continues on facing page). Microscopic appearance of livers and spleens from gp91phox−/−, iNOS−/−, and congenic wild-type mice infected with S. typhimurium. C57BL/6, gp91phox−/−, and iNOS−/− were infected as described in the legend to Fig. 2. Hematoxylin and eosin–stained sections were prepared from spleens and livers harvested at time points thereafter. Microabscesses were seen in the livers of (A) gp91phox−/−, (B) iNOS−/−, and (C) wild-type animals on day 3. Granulomatous lesions were seen within the (D and E) spleens and (F and G) livers of (D and F) iNOS−/− and (E and G) wild-type C57BL/6 mice on day 8 (original magnification: ×200). The histopathology from days 11 and 14 closely resembled that observed on day 8. Necrotic lesions were detected in the (H and I) livers and (J and K) spleens of iNOS−/− mice on day 21. Approximate original magnifications: A–G, ×400; H, ×60; I, ×200; and J–K, ×400.
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Figure 4: (continues on facing page). Microscopic appearance of livers and spleens from gp91phox−/−, iNOS−/−, and congenic wild-type mice infected with S. typhimurium. C57BL/6, gp91phox−/−, and iNOS−/− were infected as described in the legend to Fig. 2. Hematoxylin and eosin–stained sections were prepared from spleens and livers harvested at time points thereafter. Microabscesses were seen in the livers of (A) gp91phox−/−, (B) iNOS−/−, and (C) wild-type animals on day 3. Granulomatous lesions were seen within the (D and E) spleens and (F and G) livers of (D and F) iNOS−/− and (E and G) wild-type C57BL/6 mice on day 8 (original magnification: ×200). The histopathology from days 11 and 14 closely resembled that observed on day 8. Necrotic lesions were detected in the (H and I) livers and (J and K) spleens of iNOS−/− mice on day 21. Approximate original magnifications: A–G, ×400; H, ×60; I, ×200; and J–K, ×400.
Mentions: Microscopic examination of livers of C57BL/6 and congenic gp91phox−/− and iNOS−/− mice revealed the early formation of microabscesses rich in polymorphonuclear neutrophils by day 3 of infection (Fig. 4aFig. bFig. c), with more extensive lesions noted in the gp91phox−/− animals. On days 8, 11, and 14, the focal lesions in the spleens and livers of the infected C57BL/6 and iNOS−/− mice consisted mainly of mononuclear cells and were surrounded by normal tissue. This evolution of the inflammatory response 1018 occurred similarly in both iNOS−/− mice (Fig. 4d and Fig. f) and C57BL/6 mice (Fig. 4e and Fig. g), showing no iNOS dependence on the formation of mononuclear cell–rich granulomas. In several iNOS−/− mice it was visually evident that the average size of focal granulomas was larger than in congenic wild-type control mice. On day 21 of infection, granulomatous lesions present in the livers and spleens of iNOS−/− mice in the C57BL/6 background showed a variable degree of central necrosis (Fig. 4hFig. iFig. jFig. k); macroscopically visible abscesses were present in the livers and occasionally in the spleens. The histological picture in organs of wild-type 129Sv and congenic iNOS−/− mice infected with S. typhimurium C5 was similar to that described in the C57BL/6 strain background, except for the absence of central necrosis in the hepatic and splenic lesions.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, United Kingdom. pm274@cm.ac.uk

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 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.

Show MeSH
Related in: MedlinePlus