title: Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
abstract: In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kaiser
authors.affiliation: Institute of Integrative Biology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Wotzka
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Jette
authors.initials: J
authors.lastname: Lengefeld
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.affiliation: Department of Veterinary Medicine and Cambridge Infectious Diseases Consortium, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grant
authors.affiliation: Department of Environmental Systems Science, ETH Zurich, and Department of Environmental Microbiology, Eawag, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ackermann
authors.affiliation: Institute of Microbiology, Eidgenössische Technische Hochschule ETH, Zurich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects; D002432:Cecum; D002939:Ciprofloxacin / Q000494:pharmacology*; D003713:Dendritic Cells / Q000382:microbiology*; D003967:Diarrhea / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D012480:Salmonella Infections / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D002939:Ciprofloxacin