Mobile Genetic Element SCCmec-encoded psm-mec RNA Suppresses Translation of agrA and Attenuates MRSA Virulence

Abstract

Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin α (PSMα), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSMα gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSMα expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSMα comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSMα, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property.

The psm α Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

“…However, a fourth psm locus has recently been shown to directly feed into the global regulatory networks of S. aureus (34). psm-mec is a phenol-soluble modulin-encoding gene located in the staphylococcal cassette chromosome mec (SCCmec) mobile genetic element of HA-MRSA but not community-acquired MRSA (CA-MRSA) strains.…”

“…While deletion of the psm␣, psm␤, and hld loci did not cause transcriptional regulatory effects during stationary-phase culture (33), a fourth psm locus present in hospital-associated MRSA (HA-MRSA) isolates directly interacts with agrA mRNA, leading to a reduction in virulence factor production, including hla (34). These findings, together with the in vivo virulence defect described above, led us to hypothesize that a deletion of the psm loci might directly or indirectly alter Hla expression or activity in a growthdependent manner, impairing the ability of psm mutant strains to cause severe epithelial injury.…”

The importance of regulatory RNAs in Staphylococcus aureus

“…Recent work discovered that this behavior is at least partly linked to the existence of a transcription product of the psmmec gene which is located in the SCCmec of the hospital acquired MRSA (HA-MRSA) but not in the equivalent SCCmec locus of CA-MRSA (Kaito et al, 2011(Kaito et al, , 2013. Psm-mec is a bifunctional RNA, which encodes a phenol-soluble modulin a (PSMa), a cytolytic toxin.…”

“…Psm-mec is a bifunctional RNA, which encodes a phenol-soluble modulin a (PSMa), a cytolytic toxin. In addition, the psm-mec RNA inhibits translation of agrA mRNA by direct base-pairings, with the coding sequence of the mRNA (Kaito et al, 2013). It remains to be determined how psm-mec RNA is able to repress the translation of agrA mRNA.…”

“…It is more likely that duplex formation might recruit a ribonuclease to initiate mRNA degradation. Deletion of the psm-mec RNA from HA-MRSA strains increased the expression of AgrA which results in an increase of toxin production and of PSMa and enhanced virulence in mice (Kaito et al, 2013). Interestingly 25% of 325 clinical MRSA isolated in Japan contained a mutation in the psm-mec promoter and 9% did not carry psm-mec leading to high level of PSM in the supernatant.…”