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Title: Unstable chromosome rearrangements in Staphylococcus aureus cause phenotype switching associated with persistent infections.
Austin Authors: Guérillot, Romain;Kostoulias, Xenia;Donovan, Liam;Li, Lucy;Carter, Glen P;Hachani, Abderrahman;Vandelannoote, Koen;Giulieri, Stefano;Monk, Ian R;Kunimoto, Mayu;Starrs, Lora;Burgio, Gaétan;Seemann, Torsten;Peleg, Anton Y;Stinear, Timothy P;Howden, Benjamin P 
Affiliation: Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia
Doherty Applied Microbial Genomics, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia
Infection and Immunity Theme, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, 3800, Australia
Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, 3004, Australia
Microbiological Diagnostic Unit Public Health Laboratory, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia
Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, 2601, Australia
Issue Date: 2019 2019-09-16
Publication information: Proceedings of the National Academy of Sciences of the United States of America 2019; 116(40): 20135-20140
Abstract: Staphylococcus aureus small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable S. aureus SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of S. aureus linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the S. aureus chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type-like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete S. aureus genomes showed strong signatures of recombination between hsdMS genes, suggesting that analogous CI has repeatedly occurred during S. aureus evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major S. aureus lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in S. aureus associated with SCV generation and persistent infections.
DOI: 10.1073/pnas.1904861116
ORCID: 0000-0001-6046-610X
PubMed URL: 31527262
Type: Journal Article
Subjects: Staphylococcus aureus
chromosomal rearrangement
genome instability
restriction modification system
small-colony variant
Appears in Collections:Journal articles

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