Detection and analysis of methicillin-resistant human-adapted sequence type 398 allows insight into community-associated methicillin-resistant Staphylococcus aureus evolution

Abstract

BackgroundSevere 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-018-0514-9) contains supplementary material, which is available to authorized users.

Severe Disease Caused by Community-Associated MRSA ST398 Type V, Australia, 2017

“…Phylogenetic analysis showed S23009-2007 had a much closer relationship to the PVL-negative MRSA ST398 isolates from China reported by He et al than to LA-MRSA ST398 isolates from Australia (Figure) ( 7 ). These isolates are grouped within the II-GOI (group of interest) clade from the Price et al study of worldwide MRSA ST398 isolates ( 6 ).…”

“…Phylogenetic tree of MRSA sequence type (ST) 398 isolate S23009-2017, recovered from a man in Australia in 2017, and related MRSA ST398 isolates from around the world ( 2 , 6 , 7 ). The tree was constructed by using single-nucleotide polymorphism differences and is rooted with MRSA ST398 isolates containing a single Panton-Valentine leukocidin locus.…”

Surgical Site Infections Caused by Highly Virulent Methicillin-Resistant Staphylococcus aureus Sequence Type 398, China

“…From a previous study, 9–29 allelic differences can be considered possibly related, whereas > 30 are considered unrelated ( 11 ). When we compared the strains in our study to MRSA ST398 strain 4_ST398 from a hospital in Shanghai ( 12 ), we found 30–40 allelic differences between each of our 4 strains and the reference strain. There were > 150 allelic differences between the SSI strains in our study and other ST398 strains, including animal- and human-related strains, from other studies ( 7 , 13 , 14 ).…”

<p>Antimicrobial resistance, virulence genes profiling and molecular relatedness of methicillin-resistant <em>Staphylococcus aureus</em> strains isolated from hospitalized patients in Guangdong Province, China</p>

“…Generally, due to the lack of several common virulence factors, the ST398 MRSA in Europe did not cause the frequent invasive diseases in humans 45. However, a recent report indicated that the Chinese LA-MRSA ST398 isolates are far different from those of other continents, because they likely evolved from human-adapted MSSA 46. Recently, a report about the emergence of ST398 in a pig farm in Guangdong, China was published,13 which indicated the transmission of this clone between different continents.…”