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Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization.

Monack DM, Bouley DM, Falkow S - J. Exp. Med. (2004)

Bottom Line: Host-adapted strains of Salmonella are capable of establishing a persistent infection in their host often in the absence of clinical disease.Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody.Finally, chronically infected mice treated with an interferon-gamma neutralizing antibody exhibited symptoms of acute systemic infection, with evidence of high levels of bacterial replication in most tissues and high levels of fecal shedding.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. dmonack@leland.stanford.edu

ABSTRACT
Host-adapted strains of Salmonella are capable of establishing a persistent infection in their host often in the absence of clinical disease. The mouse model of Salmonella infection has primarily been used as a model for the acute systemic disease. Therefore, the sites of long-term S. typhimurium persistence in the mouse are not known nor are the mechanisms of persistent infection clearly understood. Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody. Tissues from 129sv mice colonized for 60 d contain numerous inflammatory foci and lesions with features resembling S. typhi granulomas. Tissues from mice infected for 365 d have very few organized inflammatory lesions, but the bacteria continue to persist within macrophages in the MLN and the animals generally remain disease-free. Finally, chronically infected mice treated with an interferon-gamma neutralizing antibody exhibited symptoms of acute systemic infection, with evidence of high levels of bacterial replication in most tissues and high levels of fecal shedding. Thus, interferon-gamma, which may affect the level of macrophage activation, plays an essential role in the control of the persistent S. typhimurium infection in mice.

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Histology of infected tissues from mice persistently infected with S. typhimurium and treated with IFNγ neutralizing antibody. (A) Liver, (B) lung, and (C) heart. Sections were stained with hematoxylin and eosin from a mouse infected for 260 d followed by 3 wk of IFNγ neutralizing antibody. (A) Arrow points to area of inflammation and microgranulomas. (B) Arrow points to inflammation in the pleura. (C) Arrow points to inflammation covering the epicardium. (D) Liver and (E) heart. Bacteria in sites of inflammation from serial sections were stained with antibody to S. typhimurium (green), actin was stained with phalloidin-Alexa594 (red), and nuclei of host cells were stained with Toto-3 (blue). (D) Arrow points to bacterium in the center of lesion. (Inset) Enlargement of the area of lesion containing the bacterium. (E) Arrow points to bacterium in the epicardium. (Inset) Enlargement of the area. Bars: (A) 20 μm; (B and C) 200 μm; (D and E) 100 μm.
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fig8: Histology of infected tissues from mice persistently infected with S. typhimurium and treated with IFNγ neutralizing antibody. (A) Liver, (B) lung, and (C) heart. Sections were stained with hematoxylin and eosin from a mouse infected for 260 d followed by 3 wk of IFNγ neutralizing antibody. (A) Arrow points to area of inflammation and microgranulomas. (B) Arrow points to inflammation in the pleura. (C) Arrow points to inflammation covering the epicardium. (D) Liver and (E) heart. Bacteria in sites of inflammation from serial sections were stained with antibody to S. typhimurium (green), actin was stained with phalloidin-Alexa594 (red), and nuclei of host cells were stained with Toto-3 (blue). (D) Arrow points to bacterium in the center of lesion. (Inset) Enlargement of the area of lesion containing the bacterium. (E) Arrow points to bacterium in the epicardium. (Inset) Enlargement of the area. Bars: (A) 20 μm; (B and C) 200 μm; (D and E) 100 μm.

Mentions: The ability of Salmonella to survive and/or replicate inside macrophages is dependent on the activation state of the host cell, which can be affected by host cytokines such as IFNγ. We wished to test the role of IFNγ in the persistent S. typhimurium mouse infection. Mice that had been infected with S. typhimurium for 260 d, and were not shedding, were injected intraperitoneally with either an IFNγ neutralizing antibody or an isotype-matched control antibody. 3 wk after the initial injection of the IFNγ neutralizing antibody, three of the five mice in this group began to show signs of illness such as ruffled fur and malaise. At this time the mice were killed and dissected for tissue counts. The levels of detectable S. typhimurium in the PP, spleen, liver, and gall bladder were variable in the group of mice that received the neutralizing antibody; however, all five of the mice that received the neutralizing antibody were colonized in the MLN and cecum and were shedding high levels of S. typhimurium (2.3–7.8 logs per gram of feces; Fig. 7 A). In contrast, the mice that received the control antibody were colonized at low levels in the MLN, and only two were shedding lower levels of S. typhimurium (1.6–2.9 logs per gram of feces; Fig. 7 B). Furthermore, the tissues from mice that were treated with IFNγ neutralizing antibody contained lesions in the spleen and liver that are typical of S. typhimurium infection (Fig. 8 A). Surprisingly, the three mice that appeared ill had epicarditis/pericarditis and pleuritis (Fig. 8, B and C), and this inflammation was associated with the presence of S. typhimurium (Fig. 8, D and E). In contrast, the same tissues from mice treated with the control antibody did not contain inflammation in the heart or lungs (unpublished data). Thus, we were able to reactivate the chronically carried S. typhimurium to cause an acute infection even in the presence of anti-Salmonella antibody by inactivating the host cytokine IFNγ.


Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization.

Monack DM, Bouley DM, Falkow S - J. Exp. Med. (2004)

Histology of infected tissues from mice persistently infected with S. typhimurium and treated with IFNγ neutralizing antibody. (A) Liver, (B) lung, and (C) heart. Sections were stained with hematoxylin and eosin from a mouse infected for 260 d followed by 3 wk of IFNγ neutralizing antibody. (A) Arrow points to area of inflammation and microgranulomas. (B) Arrow points to inflammation in the pleura. (C) Arrow points to inflammation covering the epicardium. (D) Liver and (E) heart. Bacteria in sites of inflammation from serial sections were stained with antibody to S. typhimurium (green), actin was stained with phalloidin-Alexa594 (red), and nuclei of host cells were stained with Toto-3 (blue). (D) Arrow points to bacterium in the center of lesion. (Inset) Enlargement of the area of lesion containing the bacterium. (E) Arrow points to bacterium in the epicardium. (Inset) Enlargement of the area. Bars: (A) 20 μm; (B and C) 200 μm; (D and E) 100 μm.
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Related In: Results  -  Collection

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fig8: Histology of infected tissues from mice persistently infected with S. typhimurium and treated with IFNγ neutralizing antibody. (A) Liver, (B) lung, and (C) heart. Sections were stained with hematoxylin and eosin from a mouse infected for 260 d followed by 3 wk of IFNγ neutralizing antibody. (A) Arrow points to area of inflammation and microgranulomas. (B) Arrow points to inflammation in the pleura. (C) Arrow points to inflammation covering the epicardium. (D) Liver and (E) heart. Bacteria in sites of inflammation from serial sections were stained with antibody to S. typhimurium (green), actin was stained with phalloidin-Alexa594 (red), and nuclei of host cells were stained with Toto-3 (blue). (D) Arrow points to bacterium in the center of lesion. (Inset) Enlargement of the area of lesion containing the bacterium. (E) Arrow points to bacterium in the epicardium. (Inset) Enlargement of the area. Bars: (A) 20 μm; (B and C) 200 μm; (D and E) 100 μm.
Mentions: The ability of Salmonella to survive and/or replicate inside macrophages is dependent on the activation state of the host cell, which can be affected by host cytokines such as IFNγ. We wished to test the role of IFNγ in the persistent S. typhimurium mouse infection. Mice that had been infected with S. typhimurium for 260 d, and were not shedding, were injected intraperitoneally with either an IFNγ neutralizing antibody or an isotype-matched control antibody. 3 wk after the initial injection of the IFNγ neutralizing antibody, three of the five mice in this group began to show signs of illness such as ruffled fur and malaise. At this time the mice were killed and dissected for tissue counts. The levels of detectable S. typhimurium in the PP, spleen, liver, and gall bladder were variable in the group of mice that received the neutralizing antibody; however, all five of the mice that received the neutralizing antibody were colonized in the MLN and cecum and were shedding high levels of S. typhimurium (2.3–7.8 logs per gram of feces; Fig. 7 A). In contrast, the mice that received the control antibody were colonized at low levels in the MLN, and only two were shedding lower levels of S. typhimurium (1.6–2.9 logs per gram of feces; Fig. 7 B). Furthermore, the tissues from mice that were treated with IFNγ neutralizing antibody contained lesions in the spleen and liver that are typical of S. typhimurium infection (Fig. 8 A). Surprisingly, the three mice that appeared ill had epicarditis/pericarditis and pleuritis (Fig. 8, B and C), and this inflammation was associated with the presence of S. typhimurium (Fig. 8, D and E). In contrast, the same tissues from mice treated with the control antibody did not contain inflammation in the heart or lungs (unpublished data). Thus, we were able to reactivate the chronically carried S. typhimurium to cause an acute infection even in the presence of anti-Salmonella antibody by inactivating the host cytokine IFNγ.

Bottom Line: Host-adapted strains of Salmonella are capable of establishing a persistent infection in their host often in the absence of clinical disease.Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody.Finally, chronically infected mice treated with an interferon-gamma neutralizing antibody exhibited symptoms of acute systemic infection, with evidence of high levels of bacterial replication in most tissues and high levels of fecal shedding.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. dmonack@leland.stanford.edu

ABSTRACT
Host-adapted strains of Salmonella are capable of establishing a persistent infection in their host often in the absence of clinical disease. The mouse model of Salmonella infection has primarily been used as a model for the acute systemic disease. Therefore, the sites of long-term S. typhimurium persistence in the mouse are not known nor are the mechanisms of persistent infection clearly understood. Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody. Tissues from 129sv mice colonized for 60 d contain numerous inflammatory foci and lesions with features resembling S. typhi granulomas. Tissues from mice infected for 365 d have very few organized inflammatory lesions, but the bacteria continue to persist within macrophages in the MLN and the animals generally remain disease-free. Finally, chronically infected mice treated with an interferon-gamma neutralizing antibody exhibited symptoms of acute systemic infection, with evidence of high levels of bacterial replication in most tissues and high levels of fecal shedding. Thus, interferon-gamma, which may affect the level of macrophage activation, plays an essential role in the control of the persistent S. typhimurium infection in mice.

Show MeSH
Related in: MedlinePlus