Pathogenic adaptation of intracellular bacteria by rewiring a cis-regulatory input function
- Suzanne E. Osbornea,
- Don Walthersb,
- Ana M. Tomljenovica,
- David T. Muldera,
- Uma Silphaduanga,
- Nancy Duonga,
- Michael J. Lowdenc,
- Mark E. Wickhamd,
- Ross F. Wallere,
- Linda J. Kenneyb and
- Brian K. Coombesa,f,1
- aThe Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8N 3Z5;
- bDepartment of Microbiology and Immunology, University of Illinois, Chicago, IL 60612;
- cDepartment of Chemistry, Dartmouth College, Hanover, NH 03755;
- dPhillips Ormonde & Fitzpatrick, 367 Collins Street, Melbourne, Victoria, 3000, Australia;
- eSchool of Botany, University of Melbourne, Melbourne, Victoria, 3010, Australia; and
- fPublic Health Agency of Canada, Laboratory for Foodborne Zoonoses, Guelph, ON, Canada N1G 3W4
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Edited by Roy Curtiss III, Arizona State University, Tempe, AZ, and approved January 8, 2009 (received for review November 17, 2008)
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.
Footnotes
- 1To whom correspondence should be addressed. E-mail: coombes{at}mcmaster.ca
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Author contributions: S.E.O., D.W., U.S., L.J.K., and B.K.C. designed research; S.E.O., D.W., A.M.T., U.S., N.D., M.J.L., R.F.W., and B.K.C. performed research; R.F.W. contributed new reagents/analytic tools; S.E.O., D.W., D.T.M., R.F.W., L.J.K., and B.K.C. analyzed data; and S.E.O., D.W., M.E.W., R.F.W., L.J.K., and B.K.C. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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Freely available online through the PNAS open access option.
