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|Title:||Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia.|
|Authors:||Giulieri, Stefano G;Baines, Sarah L;Guerillot, Romain;Seemann, Torsten;Gonçalves da Silva, Anders;Schultz, Mark;Massey, Ruth C;Holmes, Natasha E;Stinear, Timothy P;Howden, Benjamin P|
|Affiliation:||Microbiological Diagnostic Unit Public Health Laboratory, The University of Melbourne at The Doherty Institute of Infection and Immunity, Melbourne, Australia|
Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute for Infection & Immunity, Melbourne, Australia
Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
Melbourne Bioinformatics, The University of Melbourne, Melbourne, Australia
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
|Citation:||Genome medicine 2018; 10(1): 65|
|Abstract:||Large-scale genomic studies of within-host diversity in Staphylococcus aureus bacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in management of SAB. However, available comparative genomic studies of sequential SAB isolates have tended to focus on selected cases of unusually prolonged bacteraemia, where secondary antimicrobial resistance has developed. To understand bacterial genetic diversity during SAB more broadly, we applied whole genome sequencing to a large collection of sequential isolates obtained from patients with persistent or relapsing bacteraemia. After excluding genetically unrelated isolates, we performed an in-depth genomic analysis of point mutations and chromosome structural variants arising within individual SAB episodes. We show that, while adaptation pathways are heterogenous and episode-specific, isolates from persistent bacteraemia have a distinctive molecular signature, characterised by a low mutation frequency and high proportion of non-silent mutations. Analysis of structural genomic variants revealed that these often overlooked genetic events are commonly acquired during SAB. We discovered that IS256 insertion may represent the most effective driver of within-host microevolution in selected lineages, with up to three new insertion events per isolate even in the absence of other mutations. Genetic mechanisms resulting in significant phenotypic changes, such as increases in vancomycin resistance, development of small colony phenotypes, and decreases in cytotoxicity, included mutations in key genes (rpoB, stp, agrA) and an IS256 insertion upstream of the walKR operon. This study provides for the first time a large-scale analysis of within-host genomic changes during invasive S. aureus infection and describes specific patterns of adaptation that will be informative for both understanding S. aureus pathoadaptation and utilising genomics for management of complicated S. aureus infections.|
Research Support, Non-U.S. Gov't
|Appears in Collections:||Journal articles|
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