Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A regulatory cascade controls Staphylococcus aureus pathogenicity island activation

Nature Microbiology volume 6, pages 1300–1308 (2021)Cite this article

Subjects

Abstract

Staphylococcal pathogenicity islands (SaPIs) are a family of closely related mobile chromosomal islands that encode and disseminate the superantigen toxins, toxic shock syndrome toxin 1 and superantigen enterotoxin B (SEB). They are regulated by master repressors, which are counteracted by helper phage–encoded proteins, thereby inducing their excision, replication, packaging and intercell transfer. SaPIs are major components of the staphylococcal mobilome, occupying five chromosomal att sites, with many strains harbouring two or more. As regulatory interactions between co-resident SaPIs could have profound effects on the spread of superantigen pathobiology, we initiated the current study to search for such interactions. Using classical genetics, we found that, with one exception, their regulatory systems do not cross-react. The exception was SaPI3, which was originally considered defective because it could not be mobilized by any known helper phage. We show here that SaPI3 has an atypical regulatory module and is induced not by a phage but by many other SaPIs, including SaPI2, SaPIbov1 and SaPIn1, each encoding a conserved protein, Sis, which counteracts the SaPI3 repressor, generating an intracellular regulatory cascade: the co-resident SaPI, when conventionally induced by a helper phage, expresses its sis gene which, in turn, induces SaPI3, enabling it to spread. Using bioinformatics analysis, we have identified more than 30 closely related coancestral SEB-encoding SaPI3 relatives occupying the same att site and controlled by a conserved regulatory module, immA–immR–str′. This module is functionally analogous but unrelated to the typical SaPI regulatory module, stl–str. As SaPIs are phage satellites, SaPI3 and its relatives are SaPI satellites.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Helper SaPIbov1 promotes satellite SaPI3 induction and transfer.
Fig. 2: Impact of SaPI3 induction on helper SaPI replication and transfer.
Fig. 3: Sis and ImmR co-localize in vivo.
Fig. 4: The helper SaPI Sis inducer alleviates SaPI3 ImmR repression.
Fig. 5: ImmA is required for full activation of SaPI3.
Fig. 6: Model of SaPI3 activation.

Similar content being viewed by others

Data availability

No original sequence data were generated in this study. Accession codes for nucleotide sequences harbouring the studied sis homologues are as follows: SaPI1 (U93688), SaPI2 (EF010993), SaPI3 (NC_002951), SaPI4 (NC_002951), SaPI5 (NC_007793), SaPIn1 (NC_002745), SaPIbov1 (NC_007622), SaPIbov2 (AY220730), SaPIbov4 (HM211303) and SaPIbov5 (HM228919). Source data are provided with this paper.

References

  1. Lindsay, J. A., Ruzin, A., Ross, H. F., Kurepina, N. & Novick, R. P. The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus. Mol. Microbiol. 29, 527–543 (1998).

    Article  CAS  Google Scholar 

  2. Gillet, Y. et al. Association between Staphylococcus aureus strains carrying gene for Panton–Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359, 753–759 (2002).

    Article  CAS  Google Scholar 

  3. Penadés, J. R. & Christie, G. E. The phage-inducible chromosomal islands: a family of highly evolved molecular parasites. Annu. Rev. Virol. 2, 181–201 (2015).

    Article  Google Scholar 

  4. Novick, R. P. Pathogenicity islands and their role in staphylococcal biology. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.GPP3-0062-2019 (2019).

  5. Tormo, M. A. et al. Staphylococcus aureus pathogenicity island DNA is packaged in particles composed of phage proteins. J. Bacteriol. 190, 2434–2440 (2008).

    Article  CAS  Google Scholar 

  6. Tormo-Más, M. Á. et al. Moonlighting bacteriophage proteins derepress staphylococcal pathogenicity islands. Nature 465, 779–782 (2010).

    Article  Google Scholar 

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

    Article  Google Scholar 

  8. Bowring, J. et al. Pirating conserved phage mechanisms promotes promiscuous staphylococcal pathogenicity island transfer. Elife 6, e26487 (2017).

    Article  Google Scholar 

  9. Ciges-Tomas, J. R. et al. The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature. Nat. Commun. 10, 3676 (2019).

    Article  Google Scholar 

  10. Novick, R. P., Christie, G. E. & Penadés, J. R. The phage-related chromosomal islands of Gram-positive bacteria. Nat. Rev. Microbiol. 8, 541–551 (2010).

    Article  CAS  Google Scholar 

  11. Ubeda, C. et al. SaPI mutations affecting replication and transfer and enabling autonomous replication in the absence of helper phage. Mol. Microbiol. 67, 493–503 (2008).

    Article  CAS  Google Scholar 

  12. Bose, B., Auchtung, J. M., Lee, C. A. & Grossman, A. D. A conserved anti-repressor controls horizontal gene transfer by proteolysis. Mol. Microbiol. 70, 570–582 (2008).

    Article  CAS  Google Scholar 

  13. Ram, G. et al. Staphylococcal pathogenicity island interference with helper phage reproduction is a paradigm of molecular parasitism. Proc. Natl Acad. Sci. USA 109, 16300–16305 (2012).

    Article  CAS  Google Scholar 

  14. Ram, G., Chen, J., Ross, H. F. & Novick, R. P. Precisely modulated pathogenicity island interference with late phage gene transcription. Proc. Natl Acad. Sci. USA 111, 14536–14541 (2014).

    Article  CAS  Google Scholar 

  15. Fillol-Salom, A. et al. Phage-inducible chromosomal islands are ubiquitous within the bacterial universe. ISME J. 12, 2114–2128 (2018).

    Article  CAS  Google Scholar 

  16. Fillol-Salom, A. et al. Hijacking the hijackers: Escherichia coli pathogenicity islands redirect helper phage packaging for their own benefit. Mol. Cell 75, 1020–1030.e4 (2019).

    Article  CAS  Google Scholar 

  17. Ubeda, C. et al. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol. Microbiol. 56, 836–844 (2005).

    Article  CAS  Google Scholar 

  18. Ubeda, C. et al. SaPI operon I is required for SaPI packaging and is controlled by LexA. Mol. Microbiol. 65, 41–50 (2007).

    Article  CAS  Google Scholar 

  19. Quiles-Puchalt, N. et al. Staphylococcal pathogenicity island DNA packaging system involving cos-site packaging and phage-encoded HNH endonucleases. Proc. Natl Acad. Sci. USA 111, 6016–6021 (2014).

    Article  CAS  Google Scholar 

  20. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

    Article  CAS  Google Scholar 

  21. Sullivan, M. J., Petty, N. K. & Beatson, S. A. Easyfig: a genome comparison visualizer. Bioinformatics 27, 1009–1010 (2011).

    Article  CAS  Google Scholar 

  22. Bawono, P. & Heringa, J. PRALINE: a versatile multiple sequence alignment toolkit. Methods Mol. Biol. 1079, 245–262 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants MR/V000772/1, MR/M003876/1 and MR/S00940X/1 from the Medical Research Council (UK); BB/N002873/1, BB/S003835/1 and BB/V002376/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK); Wellcome Trust 201531/Z/16/Z; ERC-ADG-2014 Proposal no. 670932 Dut-signal from EU to J.R.P; and grants from the Ministry of Education (MOE), MOE2017-T2-2-163 and MOE2019-T2-2-162, to J.C. J.R.P. thanks the Royal Society and the Wolfson Foundation for providing him support through a Royal Society Wolfson Fellowship. We thank L. Lemgruber Soares of the Glasgow Imaging Facility for their support and assistance in this work.

Author information

Author notes

  1. These authors contributed equally: Andreas F. Haag, Magdalena Podkowik.

Authors and Affiliations

  1. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Andreas F. Haag, Magdalena Podkowik, Rodrigo Ibarra-Chávez & José R. Penadés

  2. Departments of Microbiology, Department of Medicine New York University School of Medicine, New York, NY, USA

    Magdalena Podkowik, Geeta Ram & Richard P. Novick

  3. Department of Food Hygiene and Consumer Health Protection, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland

    Magdalena Podkowik

  4. Instituto de Biomedicina de Valencia (IBV-CSIC) and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain

    Francisca Gallego del Sol & Alberto Marina

  5. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    John Chen

  6. Departamento de Ciencias Biomédicas, Universidad CEU Cardenal Herrera, Moncada, Spain

    José R. Penadés

  7. MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK

    José R. Penadés

Authors
  1. Andreas F. Haag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdalena Podkowik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rodrigo Ibarra-Chávez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francisca Gallego del Sol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geeta Ram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alberto Marina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard P. Novick
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José R. Penadés
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.P.N. and J.R.P. conceived the study. A.F.H., M.P., R.I-C., F.G.d.S. and G.R. conducted the experiments. A.F.H., M.P., J.C., A.M., R.P.N. and J.R.P analysed the data. R.P.N. and J.R.P wrote the manuscript.

Corresponding authors

Correspondence to Richard P. Novick or José R. Penadés.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Microbiology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–13, Tables 1–9 and References.

Reporting Summary

Peer Review Information

Supplementary Data 1

Supplementary Excel workbook containing source data and statistical analyses for Fig. 1.

Supplementary Data 2

Supplementary Excel workbook containing source data and statistical analyses for Fig. 2.

Supplementary Data 3

Supplementary Excel workbook containing source data and statistical analyses for Fig. 4.

Supplementary Data 4

Supplementary Excel workbook containing source data and statistical analyses for Fig. 5.

Supplementary Data 5

Supplementary Excel workbook containing source data and statistical analyses for Fig. S2.

Supplementary Data 6

Supplementary Excel workbook containing source data and statistical analyses for Fig. S6.

Supplementary Data 7

Supplementary Excel workbook containing source data and statistical analyses for Fig. S7.

Supplementary Data 8

Supplementary Excel workbook containing source data and statistical analyses for Fig. S8.

Supplementary Data 9

Supplementary Excel workbook containing source data and statistical analyses for Fig. S9.

Supplementary Data 10

Supplementary Excel workbook containing source data and statistical analyses for Fig. S10.

Supplementary Data 11

Supplementary Excel workbook containing source data and statistical analyses for Fig. S11.

Source data

Source Data Fig. 1

Uncropped Southern blots.

Source Data Fig. 2

Uncropped Southern blots.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haag, A.F., Podkowik, M., Ibarra-Chávez, R. et al. A regulatory cascade controls Staphylococcus aureus pathogenicity island activation. Nat Microbiol 6, 1300–1308 (2021). https://doi.org/10.1038/s41564-021-00956-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-021-00956-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology