Abstract

The capacity of microbial pathogens to alter their host tropism leading to epidemics in distinct host species populations is a global public and veterinary health concern. To investigate the molecular basis of a bacterial host-switching event in a tractable host species, we traced the evolutionary trajectory of the common rabbit clone of Staphylococcus aureus. We report that it evolved through a likely human-to-rabbit host jump over 40 years ago and that only a single naturally occurring nucleotide mutation was required and sufficient to convert a human-specific S. aureus strain into one that could infect rabbits. Related mutations were identified at the same locus in other rabbit strains of distinct clonal origin, consistent with convergent evolution. This first report of a single mutation that was sufficient to alter the host tropism of a microorganism during its evolution highlights the capacity of some pathogens to readily expand into new host species populations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Sequence Read Archive

References

  1. 1.

    , & Impact of globalization and animal trade on infectious disease ecology. Emerg. Infect. Dis. 13, 1807–1809 (2007).

  2. 2.

    et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486, 420–428 (2012).

  3. 3.

    et al. The potential for respiratory droplet–transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science 336, 1541–1547 (2012).

  4. 4.

    et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534–1541 (2012).

  5. 5.

    Livestock-associated Staphylococcus aureus: origin, evolution and public health threat. Trends Microbiol. 20, 192–198 (2012).

  6. 6.

    et al. Molecular dating of human-to-bovid host jumps by Staphylococcus aureus reveals an association with the spread of domestication. Biol. Lett. 8, 829–832 (2012).

  7. 7.

    et al. Evolutionary genomics of Staphylococcus aureus reveals insights into the origin and molecular basis of ruminant host adaptation. Genome Biol. Evol. 2, 454–466 (2010).

  8. 8.

    et al. Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 106, 19545–19550 (2009).

  9. 9.

    et al. Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock. MBio. 3, e00305–11 (2012).

  10. 10.

    et al. Adaptation of Staphylococcus aureus to ruminant and equine hosts involves SaPI-carried variants of von Willebrand factor–binding protein. Mol. Microbiol. 77, 1583–1594 (2010).

  11. 11.

    , , , & The innate immune modulators staphylococcal complement inhibitor and chemotaxis inhibitory protein of Staphylococcus aureus are located on β-hemolysin–converting bacteriophages. J. Bacteriol. 188, 1310–1315 (2006).

  12. 12.

    et al. Sip, an integrase protein with excision, circularization and integration activities, defines a new family of mobile Staphylococcus aureus pathogenicity islands. Mol. Microbiol. 49, 193–210 (2003).

  13. 13.

    et al. Global distribution and evolution of Panton-Valentine leukocidin-positive methicillin-susceptible Staphylococcus aureus, 1981–2007. J. Infect. Dis. 201, 1589–1597 (2010).

  14. 14.

    et al. International dissemination of a high virulence rabbit Staphylococcus aureus clone. J. Vet. Med. B Infect. Dis. Vet. Public Health 53, 418–422 (2006).

  15. 15.

    et al. Subpopulations of Staphylococcus aureus clonal complex 121 are associated with distinct clinical entities. PLoS One 8, e58155 (2013).

  16. 16.

    & BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evol. Biol. 7, 214 (2007).

  17. 17.

    et al. The staphylococcal toxin Panton-Valentine Leukocidin targets human C5a receptors. Cell Host Microbe 13, 584–594 (2013).

  18. 18.

    , , & EsxA and EsxB are secreted by an ESAT-6–like system that is required for the pathogenesis of Staphylococcus aureus infections. Proc. Natl. Acad. Sci. USA 102, 1169–1174 (2005).

  19. 19.

    , , , & Functional characterization of lipase in the pathogenesis of Staphylococcus aureus. Biochem. Biophys. Res. Commun. 419, 617–620 (2012).

  20. 20.

    et al. Global regulation of Staphylococcus aureus genes by Rot. J. Bacteriol. 185, 610–619 (2003).

  21. 21.

    et al. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. J. Biol. Chem. 274, 8405–8410 (1999).

  22. 22.

    et al. Staphylococcus aureus strains lacking D-alanine modifications of teichoic acids are highly susceptible to human neutrophil killing and are virulence attenuated in mice. J. Infect. Dis. 186, 214–219 (2002).

  23. 23.

    A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem. Sci. 25, 111–112 (2000).

  24. 24.

    , & A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J. Virol. 67, 1761–1764 (1993).

  25. 25.

    et al. Adaptation of HIV-1 to its human host. Mol. Biol. Evol. 24, 1853–1860 (2007).

  26. 26.

    , , & Host restriction of avian influenza viruses at the level of the ribonucleoproteins. Annu. Rev. Microbiol. 62, 403–424 (2008).

  27. 27.

    , , , & Gene loss and adaptation to hominids underlie the ancient origin of HIV-1. Cell Host Microbe 14, 85–92 (2013).

  28. 28.

    , , , & A single regulatory gene is sufficient to alter bacterial host range. Nature 458, 215–218 (2009).

  29. 29.

    et al. A single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes. EMBO J. 18, 3956–3963 (1999).

  30. 30.

    et al. Extending the host range of Listeria monocytogenes by rational protein design. Cell 129, 891–902 (2007).

  31. 31.

    et al. Moonlighting bacteriophage proteins derepress staphylococcal pathogenicity islands. Nature 465, 779–782 (2010).

  32. 32.

    et al. Phage dUTPases control transfer of virulence genes by a proto-oncogenic G protein–like mechanism. Mol. Cell 49, 947–958 (2013).

  33. 33.

    , & New vector for efficient allelic replacement in naturally nontransformable, low-GC-content, gram-positive bacteria. Appl. Environ. Microbiol. 70, 6887–6891 (2004).

  34. 34.

    , & progressiveMauve: multiple genome alignment with gene gain, loss and rearrangement. PLoS ONE 5, e11147 (2010).

  35. 35.

    et al. Detection of recombination events in bacterial genomes from large population samples. Nucleic Acids Res. 40, e6 (2012).

  36. 36.

    , & High-throughput microbial population genomics using the Cortex variation assembler. Bioinformatics 29, 275–276 (2013).

  37. 37.

    , , & Relaxed phylogenetics and dating with confidence. PLoS Biol. 4, e88 (2006).

  38. 38.

    & Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589–595 (2010).

  39. 39.

    et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).

  40. 40.

    et al. PGAP: pan-genomes analysis pipeline. Bioinformatics 28, 416–418 (2012).

  41. 41.

    & Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 104, 8478–8483 (2007).

  42. 42.

    et al. Increased cell wall teichoic acid production and D-alanylation are common phenotypes among daptomycin-resistant methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates. PLoS ONE 8, e67398 (2013).

Download references

Acknowledgements

We thank J. Etienne for helpful advice, O. Schneewind, M. Woolhouse and Í. Lasa for comments on the manuscript, C. Cervera and E. Blas for their support with the in vivo experiments, and R. Cartwright for excellent technical assistance. We are grateful to Edinburgh Genomics (Roslin Institute) for sequencing services. This work was supported by grants BIO2011-30503-C02-01, Eranet-pathogenomics PIM2010EPA-00606 and Consolider-Ingenio CSD2009-00006 from Ministerio de Ciencia e Innovación (Spain) and strategic grant funding from the University of Glasgow to J.R.P.; by a project grant (BB/I013873/1) and institute strategic grant funding from the Biotechnology and Biological Sciences Research Council (UK) to J.R.F., in addition to a doctoral training grant from the Medical Research Council (UK) to J.R.F.; and by grants AGL2011-30170-CO2-02 (Ministerio de Ciencia e Innovación, Spain) and GV2013-077 (Conselleria d'Educació, Cultura i Esport, Generalitat Valenciana) to D.V.

Author information

Author notes

    • David Viana
    • , María Comos
    •  & Paul R McAdam

    These authors contributed equally to this work.

    • J Ross Fitzgerald
    •  & José R Penadés

    These authors jointly supervised this work.

Affiliations

  1. Biomedical Research Institute, Universidad CEU Cardenal Herrera, Valencia, Spain.

    • David Viana
    •  & Laura Selva
  2. Centro de Investigación y Tecnología Animal, Instituto Valenciano de Investigaciones Agrarias (CITA-IVIA), Segorbe, Spain.

    • María Comos
  3. The Roslin Institute, University of Edinburgh, Easter Bush Campus, Edinburgh, UK.

    • Paul R McAdam
    • , Caitriona M Guinane
    •  & J Ross Fitzgerald
  4. Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.

    • Melissa J Ward
  5. Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK.

    • Beatriz M González-Muñoz
    •  & Simon J Foster
  6. Centre National de Référence des Staphylocoques, Université Lyon, Lyon, France.

    • Anne Tristan
  7. Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), Valencia, Spain.

    • José R Penadés
  8. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • José R Penadés

Authors

  1. Search for David Viana in:

  2. Search for María Comos in:

  3. Search for Paul R McAdam in:

  4. Search for Melissa J Ward in:

  5. Search for Laura Selva in:

  6. Search for Caitriona M Guinane in:

  7. Search for Beatriz M González-Muñoz in:

  8. Search for Anne Tristan in:

  9. Search for Simon J Foster in:

  10. Search for J Ross Fitzgerald in:

  11. Search for José R Penadés in:

Contributions

J.R.F. and J.R.P. conceived and designed the study. D.V., M.C. and L.S. generated and characterized the different mutant strains. P.R.M., M.J.W. and C.M.G. performed the genomic studies. B.M.G.-M. and S.J.F. measured D-Ala content. A.T. provided human strains. J.R.P., J.R.F. and S.J.F. supervised the research. J.R.F. and J.R.P. wrote the manuscript and obtained funding.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to J Ross Fitzgerald or José R Penadés.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Tables 1–6.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3219

Further reading