Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus

Abstract

Staphylococcus aureus is a bacterial pathogen known to cause infections in epidemic waves. One such epidemic was caused by a clone known as phage-type 80/81, a penicillin-resistant strain that rose to world prominence in the late 1950s. The molecular underpinnings of the phage-type 80/81 outbreak have remained unknown for decades, nor is it understood why related S. aureus clones became epidemic in hospitals in the early 1990s. To better understand the molecular basis of these epidemics, we sequenced the genomes of eight S. aureus clinical isolates representative of the phage-type 80/81 clone, the Southwest Pacific clone [a community-associated methicillin-resistant S. aureus (MRSA) clone], and contemporary S. aureus clones, all of which are genetically related and belong to the same clonal complex (CC30). Genome sequence analysis revealed that there was coincident divergence of these clones from a recent common ancestor, a finding that resolves controversy about the evolutionary history of the lineage. Notably, we identified nonsynonymous SNPs in genes encoding accessory gene regulator C (agrC) and α-hemolysin (hla)-molecules important for S. aureus virulence-that were present in virtually all contemporary CC30 hospital isolates tested. Compared with the phage-type 80/81 and Southwest Pacific clones, contemporary CC30 hospital isolates had reduced virulence in mouse infection models, the result of SNPs in agrC and hla. We conclude that agr and hla (along with penicillin resistance) were essential for world dominance of phage-type 80/81 S. aureus, whereas key SNPs in contemporary CC30 clones restrict these pathogens to hospital settings in which the host is typically compromised.

Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus

“…The current study extends the recent findings of DeLeo et al (12) who revealed the independent origin of phage 80/81 and SWP pandemics and identified mutations leading to reduced virulence among contemporary CC30 strains. The capacity to rapidly sequence the genome of large numbers of bacterial isolates can result in very enhanced insights into bacterial epidemics.…”

“…In their recent study, DeLeo and colleagues included a single EMRSA-16 isolate (MRSA252) and identified mutations in agr and hla genes, which occurred in an ancestor of MRSA252 and other contemporary CC30 isolates leading to reduced virulence in mouse models of infection (12). As proposed by the authors, these mutations may have contributed to the hospital association of contemporary CC30 isolates (4).…”

“…Given the rate of molecular evolution determined for the CC30 lineage, we calculated the time of the most recent common ancestor (MRCA) for each of the three major clades that correspond to the three pandemic CC30 clones. The date for the MRCA of the 80/81 clone was estimated as 1936 (95% HPDs, 1926(95% HPDs, -1945, the date for the MRCA of the SWP clone was estimated as 1967 (95% HPDs, 1952(95% HPDs, -1984 clone, but that each clone has evolved from a single ancestral strain, which gave rise to all three CC30 pandemics (12). In agreement with this finding, our phylogenetic analysis clearly demonstrates the independent origins of each of the three major CC30 pandemic clones.…”

“…The Southwest Pacific clone (SWP) is a contemporary PVL + community-associated MRSA clone, which has spread to several continents and which largely causes skin and soft tissue infections of otherwise healthy individuals (10,11). In contrast to phage type 80/ 81 and SWP, the EMRSA-16 (ST36) clone appears to be restricted to the hospital setting and has reduced virulence due in part to low levels of expression of cytolytic toxins (12). Along with the EMRSA-15 (ST22) clone, EMRSA-16 has been endemic in UK hospitals for over 20 y and has also been reported less commonly in other European countries, Southeast Asia, South Africa, Australia, and North America (3,(13)(14)(15)(16)(17).…”

Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity

“…In conclusion, the multiscale comparative approach used in this work provides insights into the diversity of the S. aureus species. Historical methods for classification of S. aureus strains have developed considerably from phage-typing to PFGE and MLST approaches (52). New high-throughput DNA sequencing technologies and analysis techniques will continue to improve our ability to track and distinguish pathogens.…”