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

Publication 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

  • 1,406
    Page views
  • 197
    Downloads
  • 4
    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
  1. Further reading

Further reading

    1. Genetics and Genomics
    Dilan SR Patiranage et al.
    Tools and Resources Updated

    Quinoa germplasm preserves useful and substantial genetic variation, yet it remains untapped due to a lack of implementation of modern breeding tools. We have integrated field and sequence data to characterize a large diversity panel of quinoa. Whole-genome sequencing of 310 accessions revealed 2.9 million polymorphic high confidence single nucleotide polymorphism (SNP) loci. Highland and Lowland quinoa were clustered into two main groups, with FST divergence of 0.36 and linkage disequilibrium (LD) decay of 6.5 and 49.8 kb, respectively. A genome-wide association study using multi-year phenotyping trials uncovered 600 SNPs stably associated with 17 traits. Two candidate genes are associated with thousand seed weight, and a resistance gene analog is associated with downy mildew resistance. We also identified pleiotropically acting loci for four agronomic traits important for adaptation. This work demonstrates the use of re-sequencing data of an orphan crop, which is partially domesticated to rapidly identify marker-trait association and provides the underpinning elements for genomics-enabled quinoa breeding.

    1. Developmental Biology
    2. Genetics and Genomics
    Divya Khattar et al.
    Research Article

    The tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+ progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar epithelial cells later in development. Transcription factors, including Sox9, Etv5, Irx, Mycn, and Foxp1/2 interact in complex gene regulatory networks to control proliferation and differentiation of SOX9+ progenitors. Molecular mechanisms by which these transcription factors and other signaling pathways control chromatin state to establish and maintain cell-type identity are not well-defined. Herein, we analyze paired gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) data from SOX9+ epithelial progenitor cells (EPCs) during embryonic development in Mus musculus. Widespread changes in chromatin accessibility were observed between E11.5 and E16.5, particularly at distal cis-regulatory elements (e.g. enhancers). Gene regulatory network (GRN) inference identified a common SOX9+ progenitor GRN, implicating phosphoinositide 3-kinase (PI3K) signaling in the developmental regulation of SOX9+ progenitor cells. Consistent with this model, conditional ablation of PI3K signaling in the developing lung epithelium in mouse resulted in an expansion of the SOX9+ EPC population and impaired airway epithelial cell differentiation. These data demonstrate that PI3K signaling is required for epithelial patterning during lung organogenesis, and emphasize the combinatorial power of paired RNA and ATAC seq in defining regulatory networks in development.