Decoding commensal-host communication through genetic engineering of Staphylococcus epidermidis

Commensal skin bacteria elicit potent, antigen-specific immune responses in the skin without barrier breach or visible inflammation. While microbial modulation of immune homeostasis has profound consequences for epithelial health and inflammatory skin diseases, the mechanisms of microbe-immune crosstalk in the skin are largely unknown. A key barrier to mechanistic work has been genetic intractability of one of the most prevalent skin colonists, Staphylococcus epidermidis ( S. epidermidis ). Here, we develop a novel method to create a library of mutants with defined cell envelope alterations in primary human S. epidermidis isolates. By colonizing mice with these mutants, we uncover bacterial molecules involved in the induction of defined immune signatures. Notably, we show that under conditions of physiologic colonization, S. epidermidis cell envelope glycolipids are sensed by C-type lectin receptors, likely in non-myeloid cells, in conjunction with Toll-like receptors. This combinatorial signaling determines the quality of T cell responses and results in the potential for greater specificity toward commensal microbiota than previously appreciated. Additionally, the microbial molecules required for the colonization-induced immune response are dispensable for T cells responses in a model of S. epidermidis infection, but differentially modulate innate inflammatory responses. Thus, the same microbe uses distinct sets of molecules to signal to the immune system commensal versus pathogenic behavior, and differential sensing of these microbial signals depends on host context.