Niche-specific genome degradation and convergent evolution shaping Staphylococcus aureus adaptation during severe infections

Abstract

During severe infections, Staphylococcus aureus moves from its colonising sites to blood and tissues, and is exposed to new selective pressures, thus potentially driving adaptive evolution. Previous studies have shown the key role of the agr locus in S. aureus pathoadaptation, however a more comprehensive characterisation of genetic signatures of bacterial adaptation may enable prediction of clinical outcomes and reveal new targets for treatment and prevention of these infections. Here, we measured adaptation using within-host evolution analysis of 2,590 S. aureus genomes from 396 independent episodes of infection. By capturing a comprehensive repertoire of single-nucleotide and structural genome variations, we found evidence of a distinctive evolutionary pattern within the infecting populations compared to colonising bacteria. These invasive strains had up to 20-fold enrichments for genome degradation signatures and displayed significantly convergent mutations in a distinctive set of genes, linked to antibiotic response and pathogenesis. In addition to agr-mediated adaptation we identified non-canonical, genome-wide significant loci including sucA-sucB and stp1. The prevalence of adaptive changes increased with infection extent, emphasising the clinical significance of these signatures. These findings provide a high-resolution picture of the molecular changes when S. aureus transitions from colonisation to severe infection and may inform correlation of infection outcomes with adaptation signatures.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file 1-6.The code to call, filter and annotated within-host variants and to perform the enrichment analysis is available on github at https://github.com/stefanogg/staph_adaptation_paper

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Stefano G Giulieri

    Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Romain Guérillot

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Sebastian Duchene

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Abderrahman Hachani

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8032-2154
  5. Diane Daniel

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Torsten Seemann

    Microbiological Diagnostic Unit, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Joshua S Davis

    Department of Infectious Diseases, John Hunter Hospital, Newcastle, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Steven YC Tong

    Victorian Infectious Diseases Service, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1368-8356
  9. Bernadette C Young

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6071-6770
  10. Daniel J Wilson

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0940-3311
  11. Timothy P Stinear

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Benjamin P Howden

    Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
    For correspondence
    bhowden@unimelb.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0237-1473

Funding

National Health and Medical Research Council

  • Timothy P Stinear

National Health and Medical Research Council

  • Benjamin P Howden

The University of Melbourne

  • Stefano G Giulieri

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

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Ethics

Human subjects: Ethics approval was obtained at each partecipating site to the CAMERA2 trial and written informed onsent was obtained from each participant or surrogate decision maker.

Version history

  1. Received: January 19, 2022
  2. Preprint posted: February 12, 2022 (view preprint)
  3. Accepted: June 8, 2022
  4. Accepted Manuscript published: June 14, 2022 (version 1)
  5. Version of Record published: July 8, 2022 (version 2)

Copyright

© 2022, Giulieri et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,488
    views
  • 558
    downloads
  • 23
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Stefano G Giulieri
  2. Romain Guérillot
  3. Sebastian Duchene
  4. Abderrahman Hachani
  5. Diane Daniel
  6. Torsten Seemann
  7. Joshua S Davis
  8. Steven YC Tong
  9. Bernadette C Young
  10. Daniel J Wilson
  11. Timothy P Stinear
  12. Benjamin P Howden
(2022)
Niche-specific genome degradation and convergent evolution shaping Staphylococcus aureus adaptation during severe infections
eLife 11:e77195.
https://doi.org/10.7554/eLife.77195

Share this article

https://doi.org/10.7554/eLife.77195

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Ardalan Naseri, Degui Zhi, Shaojie Zhang
    Research Article Updated

    Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Lisa Baumgartner, Jonathan J Ipsaro ... Julius Brennecke
    Research Advance

    Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin-binding patterns, likely due to interactions with various specificity factors. Previously, we showed that the chromatin-binding pattern of the HP1 protein Rhino, a crucial factor of the Drosophila PIWI-interacting RNA (piRNA) pathway, is largely defined by a DNA sequence-specific C2H2 zinc finger protein named Kipferl (Baumgartner et al., 2022). Here, we elucidate the molecular basis of the interaction between Rhino and its guidance factor Kipferl. Through phylogenetic analyses, structure prediction, and in vivo genetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying the rhinoG31D mutation phenocopy kipferl mutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile of rhinoG31D flies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.