Pathogenic adaptation of intracellular bacteria by rewiring a cis-regulatory input function.
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.
Osborne
Suzanne E
SE
The Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8N 3Z5.
Walthers
Don
D
Tomljenovic
Ana M
AM
Mulder
David T
DT
Silphaduang
Uma
U
Duong
Nancy
N
Lowden
Michael J
MJ
Wickham
Mark E
ME
Waller
Ross F
RF
Kenney
Linda J
LJ
Coombes
Brian K
BK
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
D001426:Bacterial Proteins; C119761:SsrB protein, Salmonella typhimurium; D014157:Transcription Factors