Adaptive Change Inferred from Genomic Population Analysis of the ST93 Epidemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus

Genome Biology and Evolution, Jan 2014

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem around the world. In Australia, ST93-IV[2B] is the dominant CA-MRSA clone and displays significantly greater virulence than other S. aureus. Here, we have examined the evolution of ST93 via genomic analysis of 12 MSSA and 44 MRSA ST93 isolates, collected from around Australia over a 17-year period. Comparative analysis revealed a core genome of 2.6 Mb, sharing greater than 99.7% nucleotide identity. The accessory genome was 0.45 Mb and comprised additional mobile DNA elements, harboring resistance to erythromycin, trimethoprim, and tetracycline. Phylogenetic inference revealed a molecular clock and suggested that a single clone of methicillin susceptible, Panton-Valentine leukocidin (PVL) positive, ST93 S. aureus likely spread from North Western Australia in the early 1970s, acquiring methicillin resistance at least twice in the mid 1990s. We also explored associations between genotype and important MRSA phenotypes including oxacillin MIC and production of exotoxins (α-hemolysin [Hla], δ-hemolysin [Hld], PSMα3, and PVL). High-level expression of Hla is a signature feature of ST93 and reduced expression in eight isolates was readily explained by mutations in the agr locus. However, subtle but significant decreases in Hld were also noted over time that coincided with decreasing oxacillin resistance and were independent of agr mutations. The evolution of ST93 S. aureus is thus associated with a reduction in both exotoxin expression and oxacillin MIC, suggesting MRSA ST93 isolates are under pressure for adaptive change.

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Adaptive Change Inferred from Genomic Population Analysis of the ST93 Epidemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus

Timothy P. Stinear 1 2 Kathryn E. Holt 0 Kyra Chua 1 2 5 6 Justin Stepnell 2 Kellie L. Tuck 4 Geoffrey Coombs 3 8 Paul Francis Harrison 7 Torsten Seemann 7 Benjamin P. Howden 1 2 5 6 0 Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne , Victoria, Australia 1 Department of Microbiology, Monash University , Clayton, Victoria, Australia 2 Department of Microbiology and Immunology, University of Melbourne , Victoria, Australia 3 Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Biomedical Sciences, Curtin University , Bentley, Western Australia, Australia 4 School of Chemistry, Monash University , Clayton, Victoria, Australia 5 Department of Microbiology, Austin Health , Heidelberg , Victoria, Australia 6 Austin Centre for Infection Research (ACIR), Infectious Diseases Department, Austin Health , Heidelberg , Victoria, Australia 7 Victorian Bioinformatics Consortium, Monash University , Clayton, Victoria, 3800, Australia 8 Department of Microbiology and Infectious Diseases, PathWest Laboratory Medicine WA, Royal Perth Hospital , Perth, Western Australia, Australia Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem around the world. In Australia, ST93-IV[2B] is the dominant CA-MRSA clone and displays significantly greater virulence than other S. aureus. Here, we have examined the evolution of ST93 via genomic analysis of 12 MSSA and 44 MRSA ST93 isolates, collected from around Australia over a 17-year period. Comparative analysis revealed a core genome of 2.6 Mb, sharing greater than 99.7% nucleotide identity. The accessory genome was 0.45 Mb and comprised additional mobile DNA elements, harboring resistance to erythromycin, trimethoprim, and tetracycline. Phylogenetic inference revealed a molecular clock and suggested that a single clone of methicillin susceptible, Panton-Valentine leukocidin (PVL) positive, ST93 S. aureus likely spread from North Western Australia in the early 1970s, acquiring methicillin resistance at least twice in the mid 1990s. We also explored associations between genotype and important MRSA phenotypes including oxacillin MIC and production of exotoxins (a-hemolysin [Hla], d-hemolysin [Hld], PSMa3, and PVL). High-level expression of Hla is a signature feature of ST93 and reduced expression in eight isolates was readily explained by mutations in the agr locus. However, subtle but significant decreases in Hld were also noted over time that coincided with decreasing oxacillin resistance and were independent of agr mutations. The evolution of ST93 S. aureus is thus associated with a reduction in both exotoxin expression and oxacillin MIC, suggesting MRSA ST93 isolates are under pressure for adaptive change. Introduction Methicillin-resistant Staphylococcus aureus (MRSA) strains are common throughout the world (Zinn et al. 2004) and until recently had been confined to hospitals. Over the past decade, the global emergence of community-acquired MRSA (CA-MRSA) has been a remarkable phenomenon, dominated by the rapid emergence and spread of a clone of CA-MRSA in the United States, called USA300 (Moran et al. 2006; Klevens et al. 2007; Kennedy et al. 2008). USA3000114 is ST8, SCCmec-IV and carries the genes (lukS-PV and The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. lukF-PV) encoding the Panton-Valentine leukocidin (PVL). Active case surveillance found an incidence of invasive CA-MRSA of 4.6 per 100,000 (Klevens et al. 2007). The USA300 clone has caused large numbers of severe SSTIs and necrotizing pneumonias in otherwise healthy individuals and is replacing traditional hospital clones of MRSA causing severe infections in hospitalized patients while continuing to cause serious infections in otherwise healthy individuals in the community (Seybold et al. 2006). USA300 possesses other virulence factors that include the arginine catabolic mobile element that assists with bacterial survival and is postulated to play a role in the rapid clonal spread of USA300 and its apparent hypervirulence (Diep and Otto 2008). However, it is difficult to be certain of the individual contribution of any one factor, and comparative genomic and functional assessments suggest that the increased virulence of USA300 may be due to upregulation of core virulence genes such as Hla and phenol soluble modulins (Li et al. 2009). In Australia, CA-MRSA first emerged in the remote Kimberley region of Western Australia (WA, Udo et al. 1993) with Aboriginal ethnicity as a major risk factor for CA-MRSA infection (...truncated)


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Timothy P. Stinear, Kathryn E. Holt, Kyra Chua, Justin Stepnell, Kellie L. Tuck, Geoffrey Coombs, Paul Francis Harrison, Torsten Seemann, Benjamin P. Howden. Adaptive Change Inferred from Genomic Population Analysis of the ST93 Epidemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus, Genome Biology and Evolution, 2014, pp. 366-378, 6/2, DOI: 10.1093/gbe/evu022