Staphylococcus aureus superantigens target sebaceous gland maturation to promote skin pathogenesis and colonization

Summary: Abstract Body: Atopic dermatitis (AD) is a chronic, itchy, and inflammatory skin disorder that affects children and adults with increasing prevalence, despite available treatments. AD is associated with abundant Staphylococcus aureus skin colonization, sebaceous gland abnormalities, and sebum lipid alterations. However, the interactions that dictate aberrant S. aureus colonization and sebaceous gland dysfunction to exacerbate AD pathogenesis are understudied. Using a mouse model of AD-like skin inflammation, involving epicutaneous application of S. aureus to the shaved and depilated dorsal skin for 7 days, we found that mice exposed to toxic shock syndrome toxin (TSST) superantigen developed increased epidermal thickening, cutaneous immune cell recruitment, and serum IgE production than mice exposed to TSST-deficient S. aureus. Remarkably, RNAseq analysis of infected skin revealed TSST-mediated suppression of sebocyte maturation and lipid synthesis genes, which was functionally associated with a reduction in mature sebaceous glands and increased S. aureus skin colonization. Excitingly, we observed a similar reduction in mature sebaceous glands in skin exposed to S. aureus deficient in staphylococcal enterotoxin B and staphylococcal enterotoxin C superantigens compared to parent, suggesting a conserved interaction between superantigens and sebaceous glands. Collectively, our data indicated that S. aureus superantigens promote skin colonization via inhibition of sebaceous gland maturation and sebum lipid production pathways. These findings have implications for the development of therapeutics that inhibit S. aureus colonization and restore skin homeostasis in AD and potentially other inflammatory skin diseases with S. aureus involvement. Laine Feller¹, Zhiyang Li¹, Sabrina Kline¹, Meng-Jen Wu¹, Jing Zhang¹, Yu Wang¹, Shardulendra P. Sherchand², Rajan Adhikari², M. Javad Aman², Stephen W. Tuffs³, Nathan Archer¹ 1. Dermatology, Johns Hopkins Medicine, Baltimore, MD, United States. 2. Bacteriology, AbVacc, Rockville, MD, United States. 3. Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada. Innate Immunity, Microbiology, and Microbiome