The role of interspecies recombinations in the evolution of antibiotic resistant pneumococci

  1. Joshua Charles D'Aeth  Is a corresponding author
  2. Mark P G van der Linden
  3. Lesley McGee
  4. Herminia De Lencastre
  5. Paul Turner
  6. Jae-Hoon Song
  7. Stephanie W Lo
  8. Rebecca A Gladstone
  9. Raquel Sa-Leao
  10. Kwan Soo Ko
  11. William P Hanage
  12. Robert F Breiman
  13. Bernard Beall
  14. Stephen D Bentley
  15. Nicholas J Croucher  Is a corresponding author
  16. The GPS Consortium
  1. Imperial College London, United Kingdom
  2. RWTH Aachen, Germany
  3. Centers for Disease Control and Prevention, United States
  4. Universidade Nova de Lisboa, Portugal
  5. Cambodia Oxford Medical Research Unit, Cambodia
  6. Sungkyunwan University School of Medicine, Republic of Korea
  7. Wellcome Trust Sanger Institute, United Kingdom
  8. Instituto de Tecnologia Química e Biológica, Portugal
  9. Sungkyunwan University School of Medicine, Korea (South), Republic of
  10. Harvard T.H Chan School of Public Health, United States
  11. Emory University, United States

Abstract

Multidrug-resistant Streptococcus pneumoniae emerge through the modification of core genome loci through short inter­species homologous recombinations and acquisition of gene cassettes. Both occurred in the otherwise contrasting histories of the antibiotic-resistant S. pneumoniae lineages PMEN3 and PMEN9. A single PMEN3 clade spread globally, evading vaccine-induced immunity through frequent serotype switching, whereas locally-circulating PMEN9 clades independently gained resistance. Both lineages repeatedly integrated Tn916 and Tn1207.1, conferring tetracycline and macrolide resistance respectively, through homologous recombination importing sequences originating in other species. A species-wide dataset found over 100 instances of such interspecific acquisitions of resistance cassettes and flanking homologous arms. Phylodynamic analysis of the most commonly-sampled Tn1207.1 insertion in PMEN9, originating from a commensal and disrupting a competence gene, suggested its expansion across Germany was driven by a high ratio of macrolide-to-β-lactam consumption. Hence selection from antibiotic consumption was sufficient for these atypically large recombinations to overcome species boundaries across the pneumococcal chromosome.

Data availability

All Sequencing data comes from publically available previously published datasets. All sequences used and their accession codes are available in the supporting S1 table.All figure source data has been deposited at Figshare, https://doi.org/10.6084/m9.figshare.c.5306462.v1

The following previously published data sets were used

Article and author information

Author details

  1. Joshua Charles D'Aeth

    Infectious disease epidemiology, Imperial College London, London, United Kingdom
    For correspondence
    j.daeth17@imperial.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9636-9886
  2. Mark P G van der Linden

    Institue for Medical Microbiology; National reference Center for Streptococci; University Hospital RWTH Aachen, RWTH Aachen, Aachen, Germany
    Competing interests
    No competing interests declared.
  3. Lesley McGee

    Respiratory Diseases Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    No competing interests declared.
  4. Herminia De Lencastre

    Laboratory of Molecular Genetics; Instituo de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Oeiras, Portugal
    Competing interests
    No competing interests declared.
  5. Paul Turner

    Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1013-7815
  6. Jae-Hoon Song

    Department of Medicine, Sungkyunwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    No competing interests declared.
  7. Stephanie W Lo

    Infection Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  8. Rebecca A Gladstone

    Infection Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  9. Raquel Sa-Leao

    Instituto de Tecnologia Química e Biológica, Oeiras, Portugal
    Competing interests
    No competing interests declared.
  10. Kwan Soo Ko

    Department of Molecular Cell Biology, Sungkyunwan University School of Medicine, Suwon, Korea (South), Republic of
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0978-1937
  11. William P Hanage

    Center for Communicable Disease Dynamics, Harvard T.H Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.
  12. Robert F Breiman

    Emory University, Atlanta, United States
    Competing interests
    No competing interests declared.
  13. Bernard Beall

    Respiratory Diseases Branch, Centers for Disease Control and Prevention, Atlanta, United States
    Competing interests
    No competing interests declared.
  14. Stephen D Bentley

    Infection Genomics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  15. Nicholas J Croucher

    Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
    For correspondence
    n.croucher@imperial.ac.uk
    Competing interests
    Nicholas J Croucher, has consulted for Antigen Discovery Inc. Has received an investigator-initiated award from GlaxoSmithKline..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6303-8768
  16. The GPS Consortium

Funding

Wellcome Trust (102169/Z/13/Z)

  • Joshua Charles D'Aeth

Medical Research Council (MR/R015600/1)

  • Joshua Charles D'Aeth
  • Nicholas J Croucher

Department for International Development (MR/T016434/1)

  • Joshua Charles D'Aeth
  • Nicholas J Croucher

Wellcome Trust and Royal Society (104169/Z/14/A)

  • Nicholas J Croucher

Bill and Melinda Gates Foundation (OPP1034556)

  • Stephanie W Lo
  • Rebecca A Gladstone
  • Stephen D Bentley

Wellcome Trust (098051 and 206194)

  • Stephanie W Lo
  • Rebecca A Gladstone
  • Stephen D Bentley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Paul B Rainey, Max Planck Institute for Evolutionary Biology, Germany

Version history

  1. Received: February 1, 2021
  2. Accepted: April 16, 2021
  3. Accepted Manuscript published: July 14, 2021 (version 1)
  4. Version of Record published: July 29, 2021 (version 2)
  5. Version of Record updated: August 16, 2021 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 2,092
    Page views
  • 272
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Joshua Charles D'Aeth
  2. Mark P G van der Linden
  3. Lesley McGee
  4. Herminia De Lencastre
  5. Paul Turner
  6. Jae-Hoon Song
  7. Stephanie W Lo
  8. Rebecca A Gladstone
  9. Raquel Sa-Leao
  10. Kwan Soo Ko
  11. William P Hanage
  12. Robert F Breiman
  13. Bernard Beall
  14. Stephen D Bentley
  15. Nicholas J Croucher
  16. The GPS Consortium
(2021)
The role of interspecies recombinations in the evolution of antibiotic resistant pneumococci
eLife 10:e67113.
https://doi.org/10.7554/eLife.67113

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    John F Ouyang, Kunal Mishra ... Jacques Behmoaras
    Research Article Updated

    Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1) associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single-cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin, and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarisation state within SPP1+ macrophages. Importantly, the MAM polarisation state follows a differentiation trajectory from SPP1+ macrophages and is associated with a core set of regulon activity. SPP1+ macrophages without the MAM polarisation state (SPP1+MAM-) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarisation state of SPP1+ macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Matthew T Parker, Sebastian M Fica ... Gordon Grant Simpson
    Research Article

    Eukaryotic genes are interrupted by introns that are removed from transcribed RNAs by splicing. Patterns of splicing complexity differ between species, but it is unclear how these differences arise. We used inter-species association mapping with Saccharomycotina species to correlate splicing signal phenotypes with the presence or absence of splicing factors. Here we show that variation in 5' splice site sequence preferences correlate with the presence of the U6 snRNA N6-methyladenosine methyltransferase METTL16 and the splicing factor SNRNP27K. The greatest variation in 5' splice site sequence occurred at the +4 position and involved a preference switch between adenosine and uridine. Loss of METTL16 and SNRNP27K orthologs, or a single SNRNP27K methionine residue, was associated with a preference for +4U. These findings are consistent with splicing analyses of mutants defective in either METTL16 or SNRNP27K orthologs and models derived from spliceosome structures, demonstrating that inter-species association mapping is a powerful orthogonal approach to molecular studies. We identified variation between species in the occurrence of two major classes of 5' splice sites, defined by distinct interaction potentials with U5 and U6 snRNAs, that correlates with intron number. We conclude that variation in concerted processes of 5' splice site selection by U6 snRNA is associated with evolutionary changes in splicing signal phenotypes.