Maria Sindhura John, Mahendran Chinnappan, Camille I. Sturges, Methinee Artami, Mohini Bhattacharya, Rebecca A. Keogh, J.S. Kavanaugh, Shivani Jain, Hanna Gedamu, Jessica Komarovsky, Mauricio Velasquez, Tripti Sharma, Jeffrey G. McDonald, Alexander R. Horswill, Tamia A. Harris-Tryon
Skin cells secrete testosterone, with greater amounts secreted at the skin surface of males compared with females. Males are also more susceptible to skin infections than females. Here we report that mice engineered with testosterone-deficient skin are resistant to methicillin-resistant Staphylococcus aureus infections. Testosterone promoted the expression of S. aureus cytotoxic virulence factors by activating the accessory gene regulator (agr) quorum-sensing pathway in a concentration-dependent manner and independent of quorum-sensing-activating auto-inducing peptides. Mutational analysis revealed that a functional histidine kinase AgrC in S. aureus was required for testosterone to exert its effect, with in silico evidence indicating a direct interaction between testosterone and AgrC. An isomer of testosterone, enantiomer-testosterone, that blocked bacterial quorum sensing, inhibited S. aureus-induced cytotoxicity of human cells. These findings advance our understanding of how the skin regulates bacterial virulence and reveals a potential therapeutic strategy for the management of infections. Testosterone produced by skin cells enhances Staphylococcus aureus pathogenicity by activating quorum sensing, and a stereoisomer of testosterone that blocks this interaction inhibits bacterial cytotoxicity towards human cells.