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Subtherapeutic tetracycline concentrations aggravate Salmonella Typhimurium infection by increasing bacterial virulence

Elin Verbrugghe (UGent) , Alexander Van Parys (UGent) , Roel Haesendonck (UGent) , Bregje Leyman (UGent) , Filip Boyen (UGent) , Freddy Haesebrouck (UGent) and Frank Pasmans (UGent)
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Organization
Abstract
Objectives: Antibiotics are among the most frequently prescribed drugs in human and animal medicine. With antibiotic resistance being a serious threat to veterinary and public health, the prudent use of antibiotics receives much attention. Lesswell known is that incorrect use of antimicrobial agents mayalso lead to increased bacterial virulence with the potential of a more severe clinical course of infection. Therefore, the aim of this study was to investigate the effect of subtherapeutic doses of tetracyclines on htpG virulence gene expression in Salmonella Typhimurium and on the course of salmonellosis. Methods: Salmonella strains containing an htpG-luxCDABE transcriptional fusion were constructed. Phenotype microarrays and tetracycline treatment were used to investigate their htpG expression. A Salmonella transposon mutant bank was used to identify genes involved in the induction of htpG gene expression. Finally, the in vitro results were linked to the in vivo situation using a Salmonella mouse model. Results: We demonstrate that subtherapeutic antimicrobial concentrations can exacerbate bacterial infections through direct up-regulation of bacterial virulence factors using Salmonella Typhimurium 112910a phage type 120/ad as a model organism. Phenotype microarrays showed that expression of the Salmonella Typhimurium virulence gene htpG is increased by several tetracycline antimicrobials at values below their MIC, a process that requires intact Salmonella LPS genes. Exposure of experimentally infected DBA/2J mice to subtherapeutic doxycycline concentrations resulted in htpG-mediated exacerbation of Salmonella Typhimurium infection. Conclusions: These findings show that the Salmonella isolate used in this study can respond to subtherapeutic tetracycline pressure by increasing its virulence and disease severity.
Keywords
ENTERICA SEROVAR TYPHIMURIUM, GENE-EXPRESSION, TRANSCRIPTIONAL MODULATION, IMMUNE-RESPONSE, ANTIBIOTICS, MICE, SUPPRESSION, INVASION, HTPG, PIGS

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Citation

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MLA
Verbrugghe, Elin et al. “Subtherapeutic Tetracycline Concentrations Aggravate Salmonella Typhimurium Infection by Increasing Bacterial Virulence.” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 71.8 (2016): 2158–2166. Print.
APA
Verbrugghe, E., Van Parys, A., Haesendonck, R., Leyman, B., Boyen, F., Haesebrouck, F., & Pasmans, F. (2016). Subtherapeutic tetracycline concentrations aggravate Salmonella Typhimurium infection by increasing bacterial virulence. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 71(8), 2158–2166.
Chicago author-date
Verbrugghe, Elin, Alexander Van Parys, Roel Haesendonck, Bregje Leyman, Filip Boyen, Freddy Haesebrouck, and Frank Pasmans. 2016. “Subtherapeutic Tetracycline Concentrations Aggravate Salmonella Typhimurium Infection by Increasing Bacterial Virulence.” Journal of Antimicrobial Chemotherapy 71 (8): 2158–2166.
Chicago author-date (all authors)
Verbrugghe, Elin, Alexander Van Parys, Roel Haesendonck, Bregje Leyman, Filip Boyen, Freddy Haesebrouck, and Frank Pasmans. 2016. “Subtherapeutic Tetracycline Concentrations Aggravate Salmonella Typhimurium Infection by Increasing Bacterial Virulence.” Journal of Antimicrobial Chemotherapy 71 (8): 2158–2166.
Vancouver
1.
Verbrugghe E, Van Parys A, Haesendonck R, Leyman B, Boyen F, Haesebrouck F, et al. Subtherapeutic tetracycline concentrations aggravate Salmonella Typhimurium infection by increasing bacterial virulence. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2016;71(8):2158–66.
IEEE
[1]
E. Verbrugghe et al., “Subtherapeutic tetracycline concentrations aggravate Salmonella Typhimurium infection by increasing bacterial virulence,” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 71, no. 8, pp. 2158–2166, 2016.
@article{7206278,
  abstract     = {Objectives: Antibiotics are among the most frequently prescribed drugs in human and animal medicine. With antibiotic resistance being a serious threat to veterinary and public health, the prudent use of antibiotics receives much attention. Lesswell known is that incorrect use of antimicrobial agents mayalso lead to increased bacterial virulence with the potential of a more severe clinical course of infection. Therefore, the aim of this study was to investigate the effect of subtherapeutic doses of tetracyclines on htpG virulence gene expression in Salmonella Typhimurium and on the course of salmonellosis.
Methods: Salmonella strains containing an htpG-luxCDABE transcriptional fusion were constructed. Phenotype microarrays and tetracycline treatment were used to investigate their htpG expression. A Salmonella transposon mutant bank was used to identify genes involved in the induction of htpG gene expression. Finally, the in vitro results were linked to the in vivo situation using a Salmonella mouse model.
Results: We demonstrate that subtherapeutic antimicrobial concentrations can exacerbate bacterial infections through direct up-regulation of bacterial virulence factors using Salmonella Typhimurium 112910a phage type 120/ad as a model organism. Phenotype microarrays showed that expression of the Salmonella Typhimurium virulence gene htpG is increased by several tetracycline antimicrobials at values below their MIC, a process that requires intact Salmonella LPS genes. Exposure of experimentally infected DBA/2J mice to subtherapeutic doxycycline concentrations resulted in htpG-mediated exacerbation of Salmonella Typhimurium infection.
Conclusions: These findings show that the Salmonella isolate used in this study can respond to subtherapeutic tetracycline pressure by increasing its virulence and disease severity.},
  author       = {Verbrugghe, Elin and Van Parys, Alexander and Haesendonck, Roel and Leyman, Bregje and Boyen, Filip and Haesebrouck, Freddy and Pasmans, Frank},
  issn         = {0305-7453},
  journal      = {JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY},
  keywords     = {ENTERICA SEROVAR TYPHIMURIUM,GENE-EXPRESSION,TRANSCRIPTIONAL MODULATION,IMMUNE-RESPONSE,ANTIBIOTICS,MICE,SUPPRESSION,INVASION,HTPG,PIGS},
  language     = {eng},
  number       = {8},
  pages        = {2158--2166},
  title        = {Subtherapeutic tetracycline concentrations aggravate Salmonella Typhimurium infection by increasing bacterial virulence},
  url          = {http://dx.doi.org/10.1093/jac/dkw152},
  volume       = {71},
  year         = {2016},
}

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