Methicillin resistant Staphylococcus aureus (MRSA) is one of the leading causes of hospital acquired infections and is considered as the most frequent cause of bacteraemia worldwide. In recent years, MRSA has acquired resistance to the last line antibiotic daptomycin (Dap) and this is commensurate with reduced innate immune responses to MRSA. Being at the interface between innate and adaptive immune responses, dendritic cells are thus central to the immune protection against MRSA. We have previously shown that clinical isolates resistant to Daptomycin (DapR) induced a compromised dendritic cell response to MRSA compared to Daptomycin sensitive (DapS) paired isolates. In this work we have explored the molecular mechanism by which MRSA strains impede dendritic cell activation. We have found that acquisition of daptomycin resistance in MRSA, inhibits the ability of dendritic cells to recognise the DapR MRSA via the cGAS/STING signalling pathway. The DapR MRSA does not actively inhibit the intracellular signalling pathways, but rather, the DapR MRSA fails to produce detectable cyclic dinucleotides, 3’3’-cGAMP, secreted at high levels by DapS MRSA, and which are potent stimulators of STING.
Our work, thus highlights important insights for the mechanism of differential recognition of clinical isolates of DapS and DapR MRSA by dendritic cells. These data provide clear molecular evidence for antimicrobial resistance directly regulating innate immune responses.