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 2590 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.
| Original language | English |
|---|---|
| Article number | e77809 |
| Pages (from-to) | 1-33 |
| Number of pages | 33 |
| Journal | eLife |
| Volume | 11 |
| DOIs | |
| Publication status | Published - 14 Jun 2022 |
Bibliographical note
Funding Information:We acknowledge members of the Sondek and Burke labs for their valuable feedback and technical support. We also thank Laura Herring and Josh Beri at the UNC Michael Hooker Proteomics Center for assistance with LC-MS/MS of phosphorylated kinase. This work was supported by The National Institutes of Health Grants R01-GM057391 (JS) and R01-GM098894 (QZ and JS), the Natural Science and Engineering Research Council of Canada (JEB, Discovery grant NSERC-2020–04241) and the Michael Smith Foundation for Health Research (JEB, Scholar Award 17686). ES-P was supported by a National Science Foundation Graduate Research Fellowship under Grant No. DGE-1650116.
Funding Information:
The authors declare that they have no competing interests. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. This work was supported by a Research Fellowship to BPH and TPS from the National Health and Medical Research Council, Australia. SGG was supported by a PhD scholarship of the University of Melbourne. We acknowledge the CAMERA2 Study Group for sharing sequences and clinical metadata of trial participants with multiple sequential bacteraemia strains: Nick Anagostou, David Andresen, Sophia Archuleta, Narin Bak, Alan Cass, Mark Chatfield, Alan Cheng, Jane Davies, Joshua Davis, Yael Dishon, Ravindra Dotel, Patricia Ferguson, Hong Foo, Vance Fowler, Niladri Ghosh, Timothy Gray, Stephen Guy, Natasha Holmes, Benjamin Howden, Sandra Johnson, Shirin Kalimuddin, David Lye, Stephen McBride, Genevieve McKew, Niamh Meagher, Jane Nelson, Matthew O’Sullivan, David Paterson, Mical Paul, David Price, Anna Ralph, Matthew Roberts, Owen Robinson, Ben Rogers, Naomi Runnegar, Simon Smith, Archana Sud, Steven Tong, Adrian Tramontana, Sebastian Van Hal, Genevieve Walls, Morgyn Warner, Dafna Yahav, and Barnaby Young.
Funding Information:
John E Burke: Burke reports consulting fees from Scorpion Therapeutics and Olema Oncology, and research grants from Novartis, which are all outside the scope of this work. John Sondek: Partial ownership of KXTbio, Inc which licenses the production of WH-15. The other authors declare that no competing interests exist.
Publisher Copyright:
© Giulieri et al.
