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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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Shedding of S. typhimurium in feces from persistently infected 129sv mice. A mean of 0.1 g of feces was collected from five different mice on days 114–117 after infection with SL1344. The contents were homogenized and plated on XLD plates. The CFU per gram of feces varied from day-to-day in a given mouse.
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fig2: Shedding of S. typhimurium in feces from persistently infected 129sv mice. A mean of 0.1 g of feces was collected from five different mice on days 114–117 after infection with SL1344. The contents were homogenized and plated on XLD plates. The CFU per gram of feces varied from day-to-day in a given mouse.

Mentions: S. typhimurium infection of 129sv mice induced pronounced splenomegaly (Fig. 1 A) and enlarged MLNs (Fig. 1 B), which peaked after 30–40 d and persisted for several weeks (Fig. 1 C). Spleen sizes slowly returned to a more normal size; however, there was a small, but significant increase in spleen weight compared with age-matched uninfected control spleens at 140 and 365 d after infection (Fig. 1 C). Despite the chronic presence of bacteria, most of the mice did not display any signs of acute illness such as malaise, weight loss, or ruffled fur. At 60 d, we found that the mice were still colonized at systemic sites (Table I). Although all five of the mice killed at 60 d were colonized, the bacterial burden per gram of tissue was considerably lower than mice infected for 5 d. In addition, we found some variation in the presence of S. typhimurium in different tissues: all of the mice were colonized in the MLN at 60 d; and two mice were colonized in all of the tissues tested. Three mice were shedding S. typhimurium in the feces on day 60; the presence of S. typhimurium in the feces correlated with gall bladder and cecal colonization (Table I). When we monitored additional mice for fecal shedding on four consecutive days (114–117 d after infection), we found that shedding varied from day to day in individual mice (Fig. 2) , suggesting that shedding occurs in periodic waves as Salmonella replicates. This result is similar to what has been well documented for human typhoid carriers (38–40).


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)

Shedding of S. typhimurium in feces from persistently infected 129sv mice. A mean of 0.1 g of feces was collected from five different mice on days 114–117 after infection with SL1344. The contents were homogenized and plated on XLD plates. The CFU per gram of feces varied from day-to-day in a given mouse.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Shedding of S. typhimurium in feces from persistently infected 129sv mice. A mean of 0.1 g of feces was collected from five different mice on days 114–117 after infection with SL1344. The contents were homogenized and plated on XLD plates. The CFU per gram of feces varied from day-to-day in a given mouse.
Mentions: S. typhimurium infection of 129sv mice induced pronounced splenomegaly (Fig. 1 A) and enlarged MLNs (Fig. 1 B), which peaked after 30–40 d and persisted for several weeks (Fig. 1 C). Spleen sizes slowly returned to a more normal size; however, there was a small, but significant increase in spleen weight compared with age-matched uninfected control spleens at 140 and 365 d after infection (Fig. 1 C). Despite the chronic presence of bacteria, most of the mice did not display any signs of acute illness such as malaise, weight loss, or ruffled fur. At 60 d, we found that the mice were still colonized at systemic sites (Table I). Although all five of the mice killed at 60 d were colonized, the bacterial burden per gram of tissue was considerably lower than mice infected for 5 d. In addition, we found some variation in the presence of S. typhimurium in different tissues: all of the mice were colonized in the MLN at 60 d; and two mice were colonized in all of the tissues tested. Three mice were shedding S. typhimurium in the feces on day 60; the presence of S. typhimurium in the feces correlated with gall bladder and cecal colonization (Table I). When we monitored additional mice for fecal shedding on four consecutive days (114–117 d after infection), we found that shedding varied from day to day in individual mice (Fig. 2) , suggesting that shedding occurs in periodic waves as Salmonella replicates. This result is similar to what has been well documented for human typhoid carriers (38–40).

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