Androgens modulate Staphylococcus aureus signaling and pathogenesis

Project Summary Staphylococcus aureus soft tissue and skin infections affect seven-to-ten percent of hospitalized patients and skin infections are the third most common reason for presentation to the emergency room. Most infections of the skin are caused by S. aureus, with men having higher rates of infection with S. aureus compared to women. Adding to the burden of disease posed by these pathogens has been the development of antibiotic-resistant strains of bacteria such as methicillin-resistant S. aureus (MRSA). Despite the clear pathogenic potential of S. aureus species, it asymptomatically colonizes the nasal passages of one-third of people. This duplicity is due to coordinated regulatory networks that alter virulence factor expression depending on the sensed environmental conditions. The most well-described of these is the accessory gene regulator (agr) quorum-sensing system. In this proposal we outline our recent findings that men secrete greater amounts of testosterone at the skin surface compared to women, and our preliminary data indicating that testosterone amplifies S. aureus virulence. Our hypothesis is that skin secreted testosterone promotes S. aureus virulence through activation of quorum-sensing mechanisms. To address this question, in Aim 1 we will investigate the mechanism of testosterone stimulation of S. aureus agr signaling. We will use genetic and biochemical approaches to determine how testosterone activates the agr regulon, and we will investigate the AgrC histidine kinase as the primary testosterone target. In Aim 2 we will determine the impact of testosterone on S. aureus skin infection in vivo using mouse models. We will test this phenotype using skin infection models paired with bioluminescent strains of S. aureus with and without mutations in agr components. We will also investigate genetically engineered mice with reduced androgen production in the skin. In Aim 3 we will identify the S. aureus enzymes that metabolize skin androgens over time and their impact on quorum sensing. Our preliminary findings indicate that this pathogen breaks down testosterone into androstenedione. Using bioinformatic approaches, we have identified potential androgen- degrading enzymes encoded in the S. aureus genome and we will characterize these targets using bacterial genetic and biochemical approaches. The work proposed in this application will determine how testosterone regulates S. aureus pathogenesis at the skin surface and identify novel therapeutic targets for the treatment of S. aureus.