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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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Mean anti–S. typhimurium IgG titers in persistently infected 129sv mice. S. typhimurium-infected (n = 5 for days 60 and 140; n = 4 for days 180 and 270; n = 13 for day 365) and uninfected age-matched control mice (n = 3, except for day 180). Antibody titers were determined by ELISA using killed whole S. typhimurium sonicate as antigen. (Closed diamonds) IgG titer in S. typhimurium-infected mice. (Open triangles) IgG titer in uninfected controls. Each serum was tested at least three times in triplicate.
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fig3: Mean anti–S. typhimurium IgG titers in persistently infected 129sv mice. S. typhimurium-infected (n = 5 for days 60 and 140; n = 4 for days 180 and 270; n = 13 for day 365) and uninfected age-matched control mice (n = 3, except for day 180). Antibody titers were determined by ELISA using killed whole S. typhimurium sonicate as antigen. (Closed diamonds) IgG titer in S. typhimurium-infected mice. (Open triangles) IgG titer in uninfected controls. Each serum was tested at least three times in triplicate.

Mentions: To determine whether mice chronically infected with S. typhimurium produced antibodies to the organism, serum was collected from each mouse at the time of death, and anti-Salmonella IgG antibody titers were determined by ELISA. All of the infected mice had high antibody titers, with a 10-fold increase between 60 and 140 d (Fig. 3) . At 365 d, the antibody titers of serum from infected mice ranged from 102 to 105, which were all significantly higher than the age-matched, uninfected control mice; however, the five mice that had apparently cleared the infection had lower anti-Salmonella antibody titers than the persistently infected mice (Fig. 3).


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)

Mean anti–S. typhimurium IgG titers in persistently infected 129sv mice. S. typhimurium-infected (n = 5 for days 60 and 140; n = 4 for days 180 and 270; n = 13 for day 365) and uninfected age-matched control mice (n = 3, except for day 180). Antibody titers were determined by ELISA using killed whole S. typhimurium sonicate as antigen. (Closed diamonds) IgG titer in S. typhimurium-infected mice. (Open triangles) IgG titer in uninfected controls. Each serum was tested at least three times in triplicate.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Mean anti–S. typhimurium IgG titers in persistently infected 129sv mice. S. typhimurium-infected (n = 5 for days 60 and 140; n = 4 for days 180 and 270; n = 13 for day 365) and uninfected age-matched control mice (n = 3, except for day 180). Antibody titers were determined by ELISA using killed whole S. typhimurium sonicate as antigen. (Closed diamonds) IgG titer in S. typhimurium-infected mice. (Open triangles) IgG titer in uninfected controls. Each serum was tested at least three times in triplicate.
Mentions: To determine whether mice chronically infected with S. typhimurium produced antibodies to the organism, serum was collected from each mouse at the time of death, and anti-Salmonella IgG antibody titers were determined by ELISA. All of the infected mice had high antibody titers, with a 10-fold increase between 60 and 140 d (Fig. 3) . At 365 d, the antibody titers of serum from infected mice ranged from 102 to 105, which were all significantly higher than the age-matched, uninfected control mice; however, the five mice that had apparently cleared the infection had lower anti-Salmonella antibody titers than the persistently infected mice (Fig. 3).

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