Immunity & infection
Daptomycin Resistance Mutations in Staphylococcus aureus Affect Immune Recognition and Dendritic Cell Activation
Wednesday, June 14
6:15 PM - 7:45 PM
Methicillin-resistant Staphylococcus aureus (MRSA) represents an emerging public health threat, causing significant morbidity and mortality in both communities and the hospital setting. Resistance to last line therapeutic antibiotics is on the rise and correlates to an increase in both morbidity and mortality. Recently, whole genome sequencing revealed that mutations conferring resistance to last line antibiotics daptomycin and vancomycin affect the composition of the bacterial cell membrane and cell wall. Several of these mutations concomitantly conferred a dual resistance to host antimicrobial peptides.
Here we demonstrate that the acquisition of antibiotic resistance to daptomycin is associated with a decrease in immunological recognition by dendritic cells (DCs). As the chief antigen presenting cells, DCs form a critical adaptor linking the innate recognition of microbes with the induction of highly specific adaptive responses. Using a broad panel of soluble mediators and surface activation markers as indicators of DC activation, we show that daptomycin resistant strains of MRSA are less effective at activation of DCs than their isogenic clinical pair taken prior to commencement of antibiotic therapy. We further show that point mutations in genes responsible for phospholipid biosynthesis found in daptomycin-resistant MRSA strains play a critical role in modulating this immune recognition of resistant strains by DCs. These findings provide novel insight into the pathogenesis of MRSA infections and host immune interactions. Further work is underway seeking to identify the molecular mechanisms affecting DC activation as a consequence of genomic mutations in MRSA during the course of infection.