Abstract
Outcomes of severe bacterial infections are determined by the interplay between host, pathogen, and treatments. While human genomics has provided insights into host factors impacting Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the hypothesis that bacterial pathoadaptation is a key outcome driver, we developed a genome-wide association study (GWAS) framework to identify adaptive mutations associated with treatment failure and mortality in S. aureus bacteremia (1,358 episodes). Our research highlights the potential of vancomycin-selected mutations and vancomycin minimum inhibitory concentration (MIC) as key explanatory variables to predict infection severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability <5%); however, GWASs allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine learning, we were able to quantify the predictive potential of these adaptive signatures. Our statistical genomics framework provides a powerful means to capture adaptive mutations impacting severe bacterial infections.
| Original language | English |
|---|---|
| Article number | 113069 |
| Pages (from-to) | 1-18 |
| Number of pages | 18 |
| Journal | Cell Reports |
| Volume | 42 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 26 Sept 2023 |
Bibliographical note
Funding Information:We acknowledge all the patients and healthcare providers who were involved in the ANZCOSS and VANESSA cohorts. Patients were included in the cohorts by the following investigators and centers in Australia and New Zealand: Natasha E. Holmes, Paul D. R. Johnson, and Benjamin P. Howden (Austin Health, Heidelberg); Wendy J. Munckhof (Princess Alexandra Hospital, Woolloongabba); J. Owen Robinson (Royal Perth Hospital, Perth); Tony M. Korman (Southern Health, Clayton); Matthew V.N. Sullivan (Westmead Hospital, Westmead); Tara L. Anderson and Sanchia Warren (Royal Hobart Hospital, Hobart); Sally A. Roberts (Auckland District Health Board, Auckland); S.V.H. (Liverpool Hospital, Liverpool and Royal Prince Alfred Hospital, Sydney); Allen C. Cheng (Alfred Health, Melbourne); Eugene Athan (Barwon Health, Geelong); and John D. Turnidge (Australian Commission on Safety and Quality in Healthcare, Sydney). We thank Takehiro Tomita and Susan Ballard (Microbiological Diagnostic Unit Public Health Laboratory, Melbourne) for performing whole-genome sequencing of the ANZCOSS isolates. We acknowledge the CAMERA2 Study Group for sharing sequences and clinical metadata of trial participants with multiple sequential bacteremia 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, N.E.H., 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, S.Y.C.T., Adrian Tramontana, S.V.H., Genevieve Walls, Morgyn Warner, Dafna Yahav, and Barnaby Young. This work was supported by a Research Fellowship from the National Health and Medical Research Council , Australia, to B.P.H. ( GNT1196103 ) and T.P.S. ( GNT1105525 ). S.G.G. was supported by a PhD scholarship of the University of Melbourne. A.H. was supported by the National Health and Medical Research Council, Australia ( GNT2018880 ).
Funding Information:
We acknowledge all the patients and healthcare providers who were involved in the ANZCOSS and VANESSA cohorts. Patients were included in the cohorts by the following investigators and centers in Australia and New Zealand: Natasha E. Holmes, Paul D. R. Johnson, and Benjamin P. Howden (Austin Health, Heidelberg); Wendy J. Munckhof (Princess Alexandra Hospital, Woolloongabba); J. Owen Robinson (Royal Perth Hospital, Perth); Tony M. Korman (Southern Health, Clayton); Matthew V.N. Sullivan (Westmead Hospital, Westmead); Tara L. Anderson and Sanchia Warren (Royal Hobart Hospital, Hobart); Sally A. Roberts (Auckland District Health Board, Auckland); S.V.H. (Liverpool Hospital, Liverpool and Royal Prince Alfred Hospital, Sydney); Allen C. Cheng (Alfred Health, Melbourne); Eugene Athan (Barwon Health, Geelong); and John D. Turnidge (Australian Commission on Safety and Quality in Healthcare, Sydney). We thank Takehiro Tomita and Susan Ballard (Microbiological Diagnostic Unit Public Health Laboratory, Melbourne) for performing whole-genome sequencing of the ANZCOSS isolates. We acknowledge the CAMERA2 Study Group for sharing sequences and clinical metadata of trial participants with multiple sequential bacteremia 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, N.E.H. 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, S.Y.C.T. Adrian Tramontana, S.V.H. Genevieve Walls, Morgyn Warner, Dafna Yahav, and Barnaby Young. This work was supported by a Research Fellowship from the National Health and Medical Research Council, Australia, to B.P.H. (GNT1196103) and T.P.S. (GNT1105525). S.G.G. was supported by a PhD scholarship of the University of Melbourne. A.H. was supported by the National Health and Medical Research Council, Australia (GNT2018880). Conceptualization, S.G.G. R.G. T.P.S. and B.P.H.; methodology, S.G.G. and R.G.; software, S.G.G. and T.S.; validation, S.G.G. R.G. and A.S.H.; formal analysis, S.G.G.; investigation, S.G.G. N.E.M. S.L.B. A.S.H. D.S.D. J.S.D. S.V.H. and S.Y.C.T.; resources, N.E.M. J.S.D. S.V.H. S.Y.C.T. and B.P.H.; data curation, S.G.G. N.E.M. S.L.B. D.S.D. J.S.D. S.V.H. and S.Y.C.T.; writing – original draft, S.G.G.; writing – review & editing, S.G.G. R.G. N.E.M. S.L.B. A.H. J.S.D. S.V.H. S.Y.C.T. T.P.S. and B.P.H.; visualization, S.G.G.; supervision, R.G. T.P.S. and B.P.H.; project administration, S.G.G.; funding acquisition, T.P.S. and B.P.H. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. One or more of the authors of this paper self-identifies as living with a disability.
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