Targeting host nuclear receptors for the resolution of Staphylococcus aureus Skin Infections

Methicillin-Resistant Staphylococcus aureus (MRSA) is a common cause of skin and soft tissue infections (SSTIs) in healthy patients. While usually self-resolving, prolonged MRSA SSTIs risk dissemination to other disease presentations including sepsis, endocarditis and osteomyelitis. Quick resolution of MRSA SSTIs reduces this risk. We have found that the two-phase host response to MRSA SSTIs can adequately resolve MRSA SSTIs. More importantly, the resolution phase is where the bacteria are cleared as opposed to the initial inflammatory phase. We have reported that PPAR is a critical regulator responsible for the switch from the inflammatory phase to the resolution phase. Treating animals with activators of PPAR can hasten the onset of the resolution phase and the clearance of the infection. This application seeks to solidify these observations and to define the signals that PPAR senses to become active and exploit these signals as topical treatment options. We further propose an exploratory aim in which we will document the macrophage populations and how they change over time using single cell RNA_Seq. We will see the dynamic switch from pro-inflammatory to efferocytotic macrophages and the transcriptional signatures associated with each phenotype. We will also be able to see how our treatment affects the dynamic macrophage populations during a MRSA SSTI.