title: Antibiotic treatment selects for cooperative virulence of Salmonella typhimurium.
abstract: Antibiotics are powerful therapeutics but are not equally effective against all cells in bacterial populations. Bacteria that express an antibiotic-tolerant phenotype ("persisters") can evade treatment [1]. Persisters can cause relapses of the infection after the end of the therapy [2]. It is still poorly understood whether persistence affects the evolution of bacterial virulence. During infections, persisters have been found preferentially at particular sites within the host [3, 4]. If bacterial virulence factors are required to reach such sites, treatment with antibiotics could impose selection on the expression of virulence genes, in addition to their well-established effects on bacterial resistance. Here, we report that treatment with antibiotics selects for virulence and fosters transmissibility of Salmonella Typhimurium. In a mouse model for Salmonella diarrhea, treatment with the broad-spectrum antibiotic ciprofloxacin reverses the outcome of competition between wild-type bacteria and avirulent mutants that can spontaneously arise during within-host evolution [5]. While avirulent mutants take over the gut lumen and abolish disease transmission in untreated mice, ciprofloxacin tilts the balance in favor of virulent, wild-type bacteria. This is explained by the need for virulence factors to invade gut tissues and form a persistent reservoir. Avirulent mutants remain in the gut lumen and are eradicated. Upon cessation of antibiotic treatment, tissue-lodged wild-type pathogens reseed the gut lumen and thereby facilitate disease transmissibility to new hosts. Our results suggest a general principle by which antibiotic treatment can promote cooperative virulence during within-host evolution, increase duration of transmissibility, and thereby enhance the spread of an infectious disease.
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: mederic.diard@micro.biol.ethz.ch.
authors.forename: Médéric
authors.initials: M
authors.lastname: Diard
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Sellin
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Department of Environmental Systems Science, ETH Zurich, 8092 Zurich, Switzerland; Department of Environmental Microbiology, Eawag, 8600 Dübendorf, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Arnoldini
authors.affiliation: Department of Environmental Systems Science, ETH Zurich, 8092 Zurich, Switzerland; Department of Environmental Microbiology, Eawag, 8600 Dübendorf, Switzerland. Electronic address: martin.ackermann@env.ethz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Ackermann
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: hardt@micro.biol.ethz.ch.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003967:Diarrhea / Q000382:microbiology / Q000517:prevention & control; D054884:Host-Pathogen Interactions / Q000187:drug effects; D007249:Inflammation / Q000382:microbiology / Q000473:pathology; D007422:Intestines / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D056265:Microbial Interactions; D012480:Salmonella Infections / Q000382:microbiology / Q000517:prevention & control / Q000635:transmission; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D012641:Selection, Genetic; D014774:Virulence; D037521:Virulence Factors
chemical_list: D000900:Anti-Bacterial Agents; D037521:Virulence Factors