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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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Monitoring 129sv mice persistently infected with S. typhimurium by an IVIS. 129sv mice were inoculated by oral administration of the bioluminescent labeled wild-type S. typhimurium strain, SL1344hha::Tn5lux at a dose of 108 CFU and monitored over 80 d. Days are indicated in the top left corner of each image. Light intensity is represented by a color scale in counts. Eight mice were inoculated and imaged on days 7, 23, 40, and 80. The arrow points to a mouse 2, which showed variable levels of signal over the 80 d. Mouse 4 died between 40 and 80 d. The asterisk indicates mice that were killed for analysis of MLN by confocal microscopy (e.g., mouse 2, 5, and 7).
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fig5: Monitoring 129sv mice persistently infected with S. typhimurium by an IVIS. 129sv mice were inoculated by oral administration of the bioluminescent labeled wild-type S. typhimurium strain, SL1344hha::Tn5lux at a dose of 108 CFU and monitored over 80 d. Days are indicated in the top left corner of each image. Light intensity is represented by a color scale in counts. Eight mice were inoculated and imaged on days 7, 23, 40, and 80. The arrow points to a mouse 2, which showed variable levels of signal over the 80 d. Mouse 4 died between 40 and 80 d. The asterisk indicates mice that were killed for analysis of MLN by confocal microscopy (e.g., mouse 2, 5, and 7).

Mentions: We wished to determine the site of S. typhimurium persistence in the MLN. To ensure that MLNs were taken from mice still infected with wild-type S. typhimurium, we monitored the course of infection in 129sv mice using a noninvasive method that detects bacterial signal in live animals in a semi-quantitative manner, IVIS (31). Mice were infected with a wild-type strain of S. typhimurium, SMB500, which constitutively expresses the genes necessary for bioluminescent light production (41). This strain is as virulent as wild-type SL1344 in the mouse model and retains the bioluminescent genes in the mouse infection model (unpublished data). By following the course of infection in this noninvasive manner, we found that in a given mouse, the bacterial load varied over time. For example, Fig. 5 shows a mouse that has a higher bioluminescent signal at 23 d than at 40 d. 80 d after infection, the signal increased again. Three mice that were infected with S. typhimurium for 80 d and had elevated bioluminescent signals were killed, and the MLNs from each mouse were frozen and sectioned for immunohistochemistry.


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)

Monitoring 129sv mice persistently infected with S. typhimurium by an IVIS. 129sv mice were inoculated by oral administration of the bioluminescent labeled wild-type S. typhimurium strain, SL1344hha::Tn5lux at a dose of 108 CFU and monitored over 80 d. Days are indicated in the top left corner of each image. Light intensity is represented by a color scale in counts. Eight mice were inoculated and imaged on days 7, 23, 40, and 80. The arrow points to a mouse 2, which showed variable levels of signal over the 80 d. Mouse 4 died between 40 and 80 d. The asterisk indicates mice that were killed for analysis of MLN by confocal microscopy (e.g., mouse 2, 5, and 7).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Monitoring 129sv mice persistently infected with S. typhimurium by an IVIS. 129sv mice were inoculated by oral administration of the bioluminescent labeled wild-type S. typhimurium strain, SL1344hha::Tn5lux at a dose of 108 CFU and monitored over 80 d. Days are indicated in the top left corner of each image. Light intensity is represented by a color scale in counts. Eight mice were inoculated and imaged on days 7, 23, 40, and 80. The arrow points to a mouse 2, which showed variable levels of signal over the 80 d. Mouse 4 died between 40 and 80 d. The asterisk indicates mice that were killed for analysis of MLN by confocal microscopy (e.g., mouse 2, 5, and 7).
Mentions: We wished to determine the site of S. typhimurium persistence in the MLN. To ensure that MLNs were taken from mice still infected with wild-type S. typhimurium, we monitored the course of infection in 129sv mice using a noninvasive method that detects bacterial signal in live animals in a semi-quantitative manner, IVIS (31). Mice were infected with a wild-type strain of S. typhimurium, SMB500, which constitutively expresses the genes necessary for bioluminescent light production (41). This strain is as virulent as wild-type SL1344 in the mouse model and retains the bioluminescent genes in the mouse infection model (unpublished data). By following the course of infection in this noninvasive manner, we found that in a given mouse, the bacterial load varied over time. For example, Fig. 5 shows a mouse that has a higher bioluminescent signal at 23 d than at 40 d. 80 d after infection, the signal increased again. Three mice that were infected with S. typhimurium for 80 d and had elevated bioluminescent signals were killed, and the MLNs from each mouse were frozen and sectioned for immunohistochemistry.

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