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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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Related in: MedlinePlus

Systemic infections in 129sv mice induce splenomegaly and enlarged MLN. (A) The spleen from an uninfected age-matched 129sv mouse on the left is shown next to the spleen from a 129sv mouse (spleen on the right) infected with SL1344 for 60 d. (B) MLN from the same mice as in A (right, infected MLN). (C) The weights of the spleens are plotted on the y axis, with time from infection on the x axis. Infected spleens weighed significantly more than the uninfected control spleens. P < 0.0001 for day 30; P = 0.01 for day 140; P = 0.01 for day 365 (n = 5 for each day).
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fig1: Systemic infections in 129sv mice induce splenomegaly and enlarged MLN. (A) The spleen from an uninfected age-matched 129sv mouse on the left is shown next to the spleen from a 129sv mouse (spleen on the right) infected with SL1344 for 60 d. (B) MLN from the same mice as in A (right, infected MLN). (C) The weights of the spleens are plotted on the y axis, with time from infection on the x axis. Infected spleens weighed significantly more than the uninfected control spleens. P < 0.0001 for day 30; P = 0.01 for day 140; P = 0.01 for day 365 (n = 5 for each day).

Mentions: At early times after infection, most of the mice showed histopathological lesions characteristic of S. typhimurium in the spleen, liver, PP, and MLN, which was indicative of an acute infection. The number and severity of lesions and the weights of infected spleens decreased with time (Fig. 1 C), which was indicative of convalescence. 3 of the 35 mice died over the course of the experiment, on day 165, 280, and 295, respectively, after infection; at postmortem, these mice cultured positive in the cecum, MLN, spleen, and liver for S. typhimurium (not depicted).


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)

Systemic infections in 129sv mice induce splenomegaly and enlarged MLN. (A) The spleen from an uninfected age-matched 129sv mouse on the left is shown next to the spleen from a 129sv mouse (spleen on the right) infected with SL1344 for 60 d. (B) MLN from the same mice as in A (right, infected MLN). (C) The weights of the spleens are plotted on the y axis, with time from infection on the x axis. Infected spleens weighed significantly more than the uninfected control spleens. P < 0.0001 for day 30; P = 0.01 for day 140; P = 0.01 for day 365 (n = 5 for each day).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Systemic infections in 129sv mice induce splenomegaly and enlarged MLN. (A) The spleen from an uninfected age-matched 129sv mouse on the left is shown next to the spleen from a 129sv mouse (spleen on the right) infected with SL1344 for 60 d. (B) MLN from the same mice as in A (right, infected MLN). (C) The weights of the spleens are plotted on the y axis, with time from infection on the x axis. Infected spleens weighed significantly more than the uninfected control spleens. P < 0.0001 for day 30; P = 0.01 for day 140; P = 0.01 for day 365 (n = 5 for each day).
Mentions: At early times after infection, most of the mice showed histopathological lesions characteristic of S. typhimurium in the spleen, liver, PP, and MLN, which was indicative of an acute infection. The number and severity of lesions and the weights of infected spleens decreased with time (Fig. 1 C), which was indicative of convalescence. 3 of the 35 mice died over the course of the experiment, on day 165, 280, and 295, respectively, after infection; at postmortem, these mice cultured positive in the cecum, MLN, spleen, and liver for S. typhimurium (not depicted).

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