Abstract
Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise. However, what defines virulence particularly of global CA-MRSA lineages is poorly understood. Threatening a vast population, the predominant Asian CA-MRSA lineage ST59 is of major epidemiological importance. However, there have been no molecular analyses using defined virulence gene deletion mutants in that lineage as of yet. Here, we compared virulence in skin, lung, and blood infection models of ST59 CA-MRSA isolates with geographically matched hospital-associated MRSA isolates. We selected a representative ST59 CA-MRSA isolate based on toxin expression and virulence characteristics, and produced isogenic gene deletion mutants of important CA-MRSA virulence determinants (α-toxin, PSM α, Agr) in that isolate for in-vitro and in-vivo analyses. Our results demonstrate strongly enhanced virulence of ST59 CA-MRSA over hospital-associated lineages, supporting the notion that enhanced virulence is characteristic for CA-MRSA. Furthermore, they show strong and significant contribution of Agr, α-toxin, and PSMα to pathogenesis of ST59 CA-MRSA skin, lung, and blood infection, emphasizing the value of drug development efforts targeted toward those virulence determinants.
Highlights
Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise
We compared them with all HA-MRSA isolates of ST5 (n = 141) and ST239 (n = 103) obtained at the same hospital in the same time
To obtain a representative and experimentally manageable subset of isolates, we first determined production levels of PSMα3 in all isolates from soft tissue infections (SSTIs) and lung infections, which accounted for the vast majority of infections by those isolates (ST59: SSTI 76%, lung infections 16%; ST5: SSTI 11%, lung infections 66%; ST239: SSTI 15%; lung infections 62%) (Fig. 1a)
Summary
Understanding virulence is vital for the development of novel therapeutics to target infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), which cause an ongoing epidemic in the United States and are on a global rise. Our results demonstrate strongly enhanced virulence of ST59 CA-MRSA over hospitalassociated lineages, supporting the notion that enhanced virulence is characteristic for CA-MRSA They show strong and significant contribution of Agr, α-toxin, and PSMα to pathogenesis of ST59 CA-MRSA skin, lung, and blood infection, emphasizing the value of drug development efforts targeted toward those virulence determinants. The basis of virulence in CA-MRSA is not yet completely understood, but it appears to be a combination of genetic adaptations that result in a balanced “compromise” between enhanced virulence and simultaneous maintenance of methicillin resistance. The latter is linked to the low-fitness cost, small SCCmec elements, which are characteristic for CA-MRSA and contain the methicillin resistance genes[5]. With few exceptions[11,12,13], global CA-MRSA clones have not been investigated on the molecular level, such as by using gene deletions in virulence determinants
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