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Extensive in vivo resilience of persistent Salmonella.

Barat S, Steeb B, Mazé A, Bumann D - PLoS ONE (2012)

Bottom Line: In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model.Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections.Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection.

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Chronic infections caused by persistent pathogens represent an important health problem. Here, we establish a simple practical mouse Salmonella infection model for identifying bacterial maintenance functions that are essential for persistency. In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model. Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections. Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection.

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Colonization kinetics of Salmonella enterica serovar Typhimurium purA ssaGH in systemically infected BALB/c mice.Data are shown for spleen (A) and liver (B) of individual untreated mice (open circles), and mice that were treated from day two post infection with enrofloxacin (filled circles). Statistical significance of clearance at day 6 compared to day 4 were determined by t-test of log-transformed data (**, P<0.01; n.s., not significant).
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pone-0042007-g001: Colonization kinetics of Salmonella enterica serovar Typhimurium purA ssaGH in systemically infected BALB/c mice.Data are shown for spleen (A) and liver (B) of individual untreated mice (open circles), and mice that were treated from day two post infection with enrofloxacin (filled circles). Statistical significance of clearance at day 6 compared to day 4 were determined by t-test of log-transformed data (**, P<0.01; n.s., not significant).

Mentions: Wildytpe Salmonella SL1344 grew exponentially in spleen of infected genetically susceptible BALB/c mice (Figure S1A). To generate a practical Salmonella persistency model, we constructed a Salmonella SL1344 derivative that survived but largely failed to proliferate in systemically infected mice. Specifically, we combined two mutations that had previously been shown to impair Salmonella in vivo growth: purA which blocks adenosine biosynthesis [16], and ssaGH which inactivates the SPI-2 (Salmonella pathogenicity island 2)-associated type three secretion system required for intracellular Salmonella growth and virulence [17]. Both purA and SPI-2 mutations have previously been shown to result in long-term persistence with minimal acute virulence, but our initial characterization revealed some in vivo proliferation of the individual mutants after i.v. administration (Figure S1B). In contrast, the double mutant Salmonella purA ssaGH was initially largely cleared from spleen and liver (Figure S1C) consistent with early killing during acute salmonellosis [18], but maintained largely constant bacterial tissue loads thereafter (Fig. 1A, B) suggesting limited net growth.


Extensive in vivo resilience of persistent Salmonella.

Barat S, Steeb B, Mazé A, Bumann D - PLoS ONE (2012)

Colonization kinetics of Salmonella enterica serovar Typhimurium purA ssaGH in systemically infected BALB/c mice.Data are shown for spleen (A) and liver (B) of individual untreated mice (open circles), and mice that were treated from day two post infection with enrofloxacin (filled circles). Statistical significance of clearance at day 6 compared to day 4 were determined by t-test of log-transformed data (**, P<0.01; n.s., not significant).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404010&req=5

pone-0042007-g001: Colonization kinetics of Salmonella enterica serovar Typhimurium purA ssaGH in systemically infected BALB/c mice.Data are shown for spleen (A) and liver (B) of individual untreated mice (open circles), and mice that were treated from day two post infection with enrofloxacin (filled circles). Statistical significance of clearance at day 6 compared to day 4 were determined by t-test of log-transformed data (**, P<0.01; n.s., not significant).
Mentions: Wildytpe Salmonella SL1344 grew exponentially in spleen of infected genetically susceptible BALB/c mice (Figure S1A). To generate a practical Salmonella persistency model, we constructed a Salmonella SL1344 derivative that survived but largely failed to proliferate in systemically infected mice. Specifically, we combined two mutations that had previously been shown to impair Salmonella in vivo growth: purA which blocks adenosine biosynthesis [16], and ssaGH which inactivates the SPI-2 (Salmonella pathogenicity island 2)-associated type three secretion system required for intracellular Salmonella growth and virulence [17]. Both purA and SPI-2 mutations have previously been shown to result in long-term persistence with minimal acute virulence, but our initial characterization revealed some in vivo proliferation of the individual mutants after i.v. administration (Figure S1B). In contrast, the double mutant Salmonella purA ssaGH was initially largely cleared from spleen and liver (Figure S1C) consistent with early killing during acute salmonellosis [18], but maintained largely constant bacterial tissue loads thereafter (Fig. 1A, B) suggesting limited net growth.

Bottom Line: In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model.Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections.Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection.

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

ABSTRACT
Chronic infections caused by persistent pathogens represent an important health problem. Here, we establish a simple practical mouse Salmonella infection model for identifying bacterial maintenance functions that are essential for persistency. In this model, a substantial fraction of Salmonella survived even several days of treatment with a potent fluoroquinolone antibiotic indicating stringency of the model. Evaluation of twelve metabolic defects revealed dramatically different requirements for Salmonella during persistency as compared to acute infections. Disrupted synthesis of unsaturated/cyclopropane fatty acids was the only defect that resulted in rapid Salmonella clearance suggesting that this pathway might contain suitable targets for antimicrobial chemotherapy of chronic infection.

Show MeSH
Related in: MedlinePlus