Global Changes in Staphylococcus aureus Virulence and Metabolism During Colonization of Healthy Skin

Staphylococcus aureus and its antibiotic-resistant derivative, methicillin-resistant Staphylococcus aureus (MRSA), is the leading causative agent of skin and soft tissue infections globally. S. aureus is known to transiently colonize the skin of healthy adults, and this transient colonization likely precedes an active infection. In recent years, there have been efforts to elucidate specific factors that help MRSA transition to an active infection, but the specific virulence determinants required for this transition following skin colonization are largely unknown. To address this, we utilized a new model of asymptomatic colonization of mouse skin to determine the MRSA and host skin transcriptional profiles by RNA sequencing (RNA-seq) at 5 and 24 hours post-colonization. Virulence genes encoding for numerous toxins and adhesins, and many genes involved in central metabolism were significantly upregulated during healthy skin colonization. In contrast there are few significantly changed host genes in response to MRSA colonization. Our RNA seq data were confirmed via functional in vitro and in vivo promoter-fusion assays using live bioluminescent imaging. We analyzed the promoter activity and functional capacity of FadB and FadD, respectively, which are crucial enzymatic components of the S. aureus beta-oxidation pathway, and fadD and fadA were found to modulate MRSA resistance against phosphomycin during growth in the presence of the common skin lipid, palmitic acid . Overall, our data suggest that there are global preparatory changes to the MRSA transcriptome, priming the bacteria for virulence and metabolism of host-relevant nutrients.