title: Pathogenic adaptation of intracellular bacteria by rewiring a cis-regulatory input function.
abstract: The acquisition of DNA by horizontal gene transfer enables bacteria to adapt to previously unexploited ecological niches. Although horizontal gene transfer and mutation of protein-coding sequences are well-recognized forms of pathogen evolution, the evolutionary significance of cis-regulatory mutations in creating phenotypic diversity through altered transcriptional outputs is not known. We show the significance of regulatory mutation for pathogen evolution by mapping and then rewiring a cis-regulatory module controlling a gene required for murine typhoid. Acquisition of a binding site for the Salmonella pathogenicity island-2 regulator, SsrB, enabled the srfN gene, ancestral to the Salmonella genus, to play a role in pathoadaptation of S. typhimurium to a host animal. We identified the evolved cis-regulatory module and quantified the fitness gain that this regulatory output accrues for the bacterium using competitive infections of host animals. Our findings highlight a mechanism of pathogen evolution involving regulatory mutation that is selected because of the fitness advantage the new regulatory output provides the incipient clones.
authors.affiliation: The Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8N 3Z5.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Osborne
authors.forename: Don
authors.initials: D
authors.lastname: Walthers
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tomljenovic
authors.forename: David T
authors.initials: DT
authors.lastname: Mulder
authors.forename: Uma
authors.initials: U
authors.lastname: Silphaduang
authors.forename: Nancy
authors.initials: N
authors.lastname: Duong
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lowden
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wickham
authors.forename: Ross F
authors.initials: RF
authors.lastname: Waller
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Kenney
authors.forename: Brian K
authors.initials: BK
authors.lastname: Coombes
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D054884:Host-Pathogen Interactions; D042541:Intracellular Space / Q000382:microbiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012475:Salmonella / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014435:Typhoid Fever / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C119761:SsrB protein, Salmonella typhimurium; D014157:Transcription Factors