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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. Liver and spleen sections were stained with hematoxylin and eosin. (A) Liver section from mouse infected for 60 d. Arrows point to multiple areas of inflammation and microgranulomas. (B) Liver section form mouse infected for 365 d. Arrow points to a focal granuloma. (C) Section of spleen infected for 60 d. Arrow shows accumulation of PMN in red pulp. (D) Section of spleen infected for 140 d. Arrow shows accumulation of macrophages. (E) Section of liver infected for 365 d. Bars: (A and B) 0.1 mm; (C–E) 20 μm.
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fig4: Histology of infected tissues from mice persistently infected with S. typhimurium. Liver and spleen sections were stained with hematoxylin and eosin. (A) Liver section from mouse infected for 60 d. Arrows point to multiple areas of inflammation and microgranulomas. (B) Liver section form mouse infected for 365 d. Arrow points to a focal granuloma. (C) Section of spleen infected for 60 d. Arrow shows accumulation of PMN in red pulp. (D) Section of spleen infected for 140 d. Arrow shows accumulation of macrophages. (E) Section of liver infected for 365 d. Bars: (A and B) 0.1 mm; (C–E) 20 μm.

Mentions: Histopathological studies were performed to examine the consequences of chronic S. typhimurium infection on tissue integrity, inflammation, and lesion formation. Histopathological lesions were more frequent in the spleen, liver, and MLNs at 60 d after oral inoculation than at 365 d (Fig. 4, A and B) . The tissues from mice infected for 60 d contained typical foci of necrosis, microgranulomas, or accumulations of PMNs (Fig. 4 C). At 140 d, discrete lesions were scarce in the liver and spleen. These rare inflammatory foci consisted predominantly of macrophages with minimal central necrosis (Fig. 4 D). By 365 d, the focal granulomas were not significantly different than 140 d, but they tended to have increased numbers of lymphocytes and large mononuclear cells surrounding central areas of tightly opposed macrophages (Fig. 4 E).


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. Liver and spleen sections were stained with hematoxylin and eosin. (A) Liver section from mouse infected for 60 d. Arrows point to multiple areas of inflammation and microgranulomas. (B) Liver section form mouse infected for 365 d. Arrow points to a focal granuloma. (C) Section of spleen infected for 60 d. Arrow shows accumulation of PMN in red pulp. (D) Section of spleen infected for 140 d. Arrow shows accumulation of macrophages. (E) Section of liver infected for 365 d. Bars: (A and B) 0.1 mm; (C–E) 20 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211772&req=5

fig4: Histology of infected tissues from mice persistently infected with S. typhimurium. Liver and spleen sections were stained with hematoxylin and eosin. (A) Liver section from mouse infected for 60 d. Arrows point to multiple areas of inflammation and microgranulomas. (B) Liver section form mouse infected for 365 d. Arrow points to a focal granuloma. (C) Section of spleen infected for 60 d. Arrow shows accumulation of PMN in red pulp. (D) Section of spleen infected for 140 d. Arrow shows accumulation of macrophages. (E) Section of liver infected for 365 d. Bars: (A and B) 0.1 mm; (C–E) 20 μm.
Mentions: Histopathological studies were performed to examine the consequences of chronic S. typhimurium infection on tissue integrity, inflammation, and lesion formation. Histopathological lesions were more frequent in the spleen, liver, and MLNs at 60 d after oral inoculation than at 365 d (Fig. 4, A and B) . The tissues from mice infected for 60 d contained typical foci of necrosis, microgranulomas, or accumulations of PMNs (Fig. 4 C). At 140 d, discrete lesions were scarce in the liver and spleen. These rare inflammatory foci consisted predominantly of macrophages with minimal central necrosis (Fig. 4 D). By 365 d, the focal granulomas were not significantly different than 140 d, but they tended to have increased numbers of lymphocytes and large mononuclear cells surrounding central areas of tightly opposed macrophages (Fig. 4 E).

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