title: Internalization of Salmonella by macrophages induces formation of nonreplicating persisters.
abstract: Many bacterial pathogens cause persistent infections despite repeated antibiotic exposure. Bacterial persisters are antibiotic-tolerant cells, but little is known about their growth status and the signals and pathways leading to their formation in infected tissues. We used fluorescent single-cell analysis to identify Salmonella persisters during infection. These were part of a nonreplicating population formed immediately after uptake by macrophages and were induced by vacuolar acidification and nutritional deprivation, conditions that also induce Salmonella virulence gene expression. The majority of 14 toxin-antitoxin modules contributed to intracellular persister formation. Some persisters resumed intracellular growth after phagocytosis by naïve macrophages. Thus, the vacuolar environment induces phenotypic heterogeneity, leading to either bacterial replication or the formation of nonreplicating persisters that could provide a reservoir for relapsing infection.
authors.affiliation: Section of Microbiology, Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Helaine
authors.forename: Angela M
authors.initials: AM
authors.lastname: Cheverton
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Watson
authors.forename: Laura M
authors.initials: LM
authors.lastname: Faure
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Matthews
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000992:Antitoxins / Q000235:genetics; D001427:Bacterial Toxins / Q000235:genetics; D002439:Cefotaxime / Q000494:pharmacology; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology*; D008643:Mesentery / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009876:Operon / Q000235:genetics; D010587:Phagocytosis; D011755:Pyrophosphatases / Q000235:genetics; D012008:Recurrence; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D000992:Antitoxins; D001427:Bacterial Toxins; C027627:guanosine-3',5'-bis(diphosphate) 3'-pyrophosphatase; D011755:Pyrophosphatases; D002439:Cefotaxime