title: Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy.
abstract: Antibiotic therapy often fails to eliminate a fraction of transiently refractory bacteria, causing relapses and chronic infections. Multiple mechanisms can induce such persisters with high antimicrobial tolerance in vitro, but their in vivo relevance remains unclear. Using a fluorescent growth rate reporter, we detected extensive phenotypic variation of Salmonella in host tissues. This included slow-growing subsets as well as well-nourished fast-growing subsets driving disease progression. Monitoring of Salmonella growth and survival during chemotherapy revealed that antibiotic killing correlated with single-cell division rates. Nondividing Salmonella survived best but were rare, limiting their impact. Instead, most survivors originated from abundant moderately growing, partially tolerant Salmonella. These data demonstrate that host tissues diversify pathogen physiology, with major consequences for disease progression and control.
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Claudi
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; BASF SE, 67056 Ludwigshafen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Spröte
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Chirkova
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Personnic
authors.affiliation: FACS Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Zankl
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Nura
authors.initials: N
authors.lastname: Schürmann
authors.affiliation: Proteomics Core Facility, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address: dirk.bumann@unibas.ch.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bumann
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001426:Bacterial Proteins / Q000032:analysis; D000077422:Enrofloxacin; D024841:Fluoroquinolones / Q000008:administration & dosage*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D061848:Optical Imaging / Q000379:methods*; D020543:Proteome / Q000032:analysis; D012486:Salmonella typhimurium / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D014435:Typhoid Fever / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D024841:Fluoroquinolones; D020543:Proteome; D000077422:Enrofloxacin