Skin testosterone fuels MRSA pathogenesis via quorum sensing and reveals testosterone antagonism as a therapeutic strategy

Summary: Skin cells have the capacity to secrete testosterone, with greater amounts of testosterone secreted at the skin surface in males compared to females. Males are also more susceptible to skin infections that females. We now find that mice engineered with testosterone-deficient skin are resistant to methicillin resistant <i>S. aureus </i>(MRSA) skin infections. Moreover, testosterone directly stimulates MRSA to express virulence factors that are required for skin colonization through the activation of a bacterial communication system called quorum sensing. Testosterone stimulation of bacterial quorum sensing is concentration dependent and can circumvent other inhibitory signals in the environment. Notably, we have also uncovered that an isomer of testosterone, <i>enantiomer-</i>testosterone, blocks bacterial quorum sensing and inhibits the pathogenesis of MRSA. Taken together, these findings are a mechanistic advance of our understanding of how the skin regulates bacteria and provides a novel therapeutic strategy for the management of antibiotic-resistant bacterial infections. Maria Sindhura John⁵, Mahendran Chinnappan⁵, Camille Sturges⁵, Shivani Jain⁵, Hanna Gedamu⁵, Jessica Komarovsky⁵, Mauricio Velasquez¹, Methinee Artami⁵, Mohini Bhattacharya², Rebecca A. Keogh², Jeffrey Kavanaugh², Tripti Sharma⁶, Jeffrey McDonald³, Alexander Horswill², Tamia Harris-Tryon⁴ 1. Center for Human Nutrition,, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 2. Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, United States. 3. Center for Human Nutrition and Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 4. Department of Dermatology and Immunology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 5. Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX, United States. 6. Childrens Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX, United States. Innate Immunity, Microbiology, and Microbiome