title: Attenuation of in vitro host-pathogen interactions in quinolone-resistant Salmonella Typhi mutants.
abstract: OBJECTIVE
  The relationship between quinolone resistance acquisition and invasion impairment has been studied in some Salmonella enterica serovars. However, little information has been reported regarding the invasive human-restricted pathogen Salmonella Typhi. The aim of this study was to investigate the molecular mechanisms of quinolone resistance acquisition and its impact on virulence in this serovar.
  
  
  METHODS
  Two antibiotic-resistant mutants (Ty_c1 and Ty_c2) were generated from a Salmonella Typhi clinical isolate (Ty_wt). The three strains were compared in terms of antimicrobial susceptibility, molecular mechanisms of resistance, gene expression of virulence-related factors, ability to invade eukaryotic cells (human epithelial cells and macrophages) and cytokine production.
  
  
  RESULTS
  Multidrug resistance in Ty_c2 was attributed to AcrAB/TolC overproduction, decreased OmpF (both mediated by the mar regulon) and decreased OmpC. The two mutants showed a gradually reduced expression of virulence-related genes (invA, hilA, hilD, fliC and fimA), correlating with decreased motility, reduced infection of HeLa cells and impaired uptake by and intracellular survival in human macrophages. Moreover, Ty_c2 also showed reduced tviA expression. Additionally, we revealed a significant reduction in TNF-α and IL-1β production and decreased NF-κB activation.
  
  
  CONCLUSIONS
  In this study, we provide an in-depth characterization of the molecular mechanisms of antibiotic resistance in the Salmonella Typhi serovar and evidence that acquisition of antimicrobial resistance is concomitantly detected with a loss of virulence (epithelial cell invasion, macrophage phagocytosis and cytokine production). We suggest that the low prevalence of clinical isolates of Salmonella Typhi highly resistant to ciprofloxacin is due to poor immunogenicity and impaired dissemination ability of these isolates.
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Rosselló 149-153 Barcelona, 08036, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ballesté-Delpierre
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Rosselló 149-153 Barcelona, 08036, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fàbrega
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Rosselló 149-153 Barcelona, 08036, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Ferrer-Navarro
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York City, NY 10032, USA.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Mathur
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York City, NY 10032, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Rosselló 149-153 Barcelona, 08036, Spain jvila@ub.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Vila
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004705:Endocytosis; D004847:Epithelial Cells / Q000382:microbiology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology*; D012485:Salmonella typhi / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D015363:Quinolones; D037521:Virulence Factors