Background: Severe infections with highly virulent community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are a global problem. However, the molecular events defining the evolution of CA-MRSA are still poorly understood. MRSA of sequence type (ST) 398 is known to frequently infect livestock, while ST398 isolates infecting humans are commonly methicillin-susceptible or represent MRSA originating from livestock-associated (LA)-MRSA. Methods: We used whole genome sequencing of newly detected CA-MRSA ST398 isolates, in comparison to geographically matched LA-MRSA and methicillin-sensitive ST398, to determine their evolutionary history. Furthermore, we used phenotypic analyses including animal infection models to gain insight into the evolution of virulence in these CA-MRSA isolates. Finally, we determined methicillin resistance and expression of the methicillin resistance-conferring gene mecA and its penicillin-binding protein product, PBP2a, in a large series of CA-MRSA strains of divergent STs. Results: We report several cases of severe and fatal infections due to ST398 CA-MRSA. The responsible isolates showed the typical genetic characteristics reported for human-adapted methicillin-sensitive ST398. Whole genome sequencing demonstrated that they evolved from human-adapted, methicillin-susceptible clones on several different occasions. Importantly, the isolates had not undergone consistent genetic alterations or changes in virulence as compared to their methicillin-susceptible predecessors. Finally, we observed dramatically and consistently lower methicillin resistance and expression of the resistance gene mecA, as compared to hospital-associated MRSA strains, in a diverse selection of CA-MRSA strains. Conclusions: Our study presents evidence for the development of highly virulent human-adapted ST398 CA-MRSA isolates from methicillin-susceptible predecessors. Notably, our investigation indicates that, in contrast to widespread notions, the development of CA-MRSA is not necessarily associated with the acquisition of specific virulence genes or other virulence-increasing changes. Rather, our findings emphasize the importance of the CA-MRSA-characteristic staphylococcal cassette chromosome mec types, which provide only low-level methicillin resistance, for that process. Our findings are of particular importance for the diagnosis of CA-MRSA, inasmuch as they indicate that the presence of specific virulence genes cannot generally be used for that purpose.
[1]Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Lab Med, 160 Pujian Rd, Shanghai 200127, Peoples R China.
[2]Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, 2005 Songhu Rd, Shanghai 200438, Peoples R China.
[3]Fudan Univ, Sch Life Sci, Ctr Evolutionary Biol, 2005 Songhu Rd, Shanghai 200438, Peoples R China.
[4]Fudan Univ, Inst Biomed Sci, 2005 Songhu Rd, Shanghai 200438, Peoples R China.
[5]NIAID, Pathogen Mol Genet Sect, Lab Bacteriol, NIH, 50 South Dr, Bethesda, MD 20814 USA.
[6]Shanghai Inst Vet Drug & Feeds Control, 855 Hongjing Rd, Shanghai 201103, Peoples R China.
[7]Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Dept Lab Med, 1678 East Rd, Shanghai 200127, Peoples R China.
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