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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 four compromised mutants in spleen (open circles) and liver (filled circles).Small residual colonization levels after seven days of infection suggested that all shown genes contributed to Salmonella survival but were not absolutely essential. Statistical significance of clearance at day 7 compared to day 1 in spleen was determined by t-test of log-transformed data (***, P<0.001).
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pone-0042007-g003: Colonization kinetics of four compromised mutants in spleen (open circles) and liver (filled circles).Small residual colonization levels after seven days of infection suggested that all shown genes contributed to Salmonella survival but were not absolutely essential. Statistical significance of clearance at day 7 compared to day 1 in spleen was determined by t-test of log-transformed data (***, P<0.001).

Mentions: In contrast to all these cases, two mutations, asd and gutQ yrbH, showed moderate phenotypes in our model (Fig. 3). asd encoding aspartate semialdehyde dehydrogenase is required for biosynthesis of the cell-wall peptidoglycan component diaminopimelic acid. A Salmonella asd strain spontaneously lyses in vitro and is completely cleared within one day from systemically infected mice [23]. However, Salmonella purA ssaGH asd was only partially cleared during the first day post infection which might reflect residual proliferation of some Salmonella and/or difficulties in establishing a suitable systemic niche [18]. Thereafter, this strain persisted at slowly declining levels in spleen. This could reflect non-essentiality of cell-wall synthesis for non-growing bacteria [19]. In contrast, liver loads rapidly declined suggesting a substantial fraction of Salmonella purA ssaGH with active cell-wall turnover/growth in liver. Similarly, Salmonella purA ssaGH gutQ yrbH that required supplementation with the lipopolysacharide precursor arabinose-5-phosphate to grow in vitro [29] and was highly attenuated during acute infections (our unpublished data), maintained high levels in spleen but was cleared from liver suggesting limited lipopolysaccharide demands during Salmonella persistency. Both genes thus were unsuitable as targets.


Extensive in vivo resilience of persistent Salmonella.

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

Colonization kinetics of four compromised mutants in spleen (open circles) and liver (filled circles).Small residual colonization levels after seven days of infection suggested that all shown genes contributed to Salmonella survival but were not absolutely essential. Statistical significance of clearance at day 7 compared to day 1 in spleen was determined by t-test of log-transformed data (***, P<0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042007-g003: Colonization kinetics of four compromised mutants in spleen (open circles) and liver (filled circles).Small residual colonization levels after seven days of infection suggested that all shown genes contributed to Salmonella survival but were not absolutely essential. Statistical significance of clearance at day 7 compared to day 1 in spleen was determined by t-test of log-transformed data (***, P<0.001).
Mentions: In contrast to all these cases, two mutations, asd and gutQ yrbH, showed moderate phenotypes in our model (Fig. 3). asd encoding aspartate semialdehyde dehydrogenase is required for biosynthesis of the cell-wall peptidoglycan component diaminopimelic acid. A Salmonella asd strain spontaneously lyses in vitro and is completely cleared within one day from systemically infected mice [23]. However, Salmonella purA ssaGH asd was only partially cleared during the first day post infection which might reflect residual proliferation of some Salmonella and/or difficulties in establishing a suitable systemic niche [18]. Thereafter, this strain persisted at slowly declining levels in spleen. This could reflect non-essentiality of cell-wall synthesis for non-growing bacteria [19]. In contrast, liver loads rapidly declined suggesting a substantial fraction of Salmonella purA ssaGH with active cell-wall turnover/growth in liver. Similarly, Salmonella purA ssaGH gutQ yrbH that required supplementation with the lipopolysacharide precursor arabinose-5-phosphate to grow in vitro [29] and was highly attenuated during acute infections (our unpublished data), maintained high levels in spleen but was cleared from liver suggesting limited lipopolysaccharide demands during Salmonella persistency. Both genes thus were unsuitable as targets.

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