ABSTRACT The goal of this multi-PI project is to understand how Staphylococcus spp. bind to the skin surface. Although S. aureus has the capability to cause significant disease in humans, most Staphylococcus spp. do not cause disease but instead act as commensals or mutualists and adhere to the skin surface providing beneficial aspects to the host. These benefits include inhibition of pathogen colonization by synthesis of unique antimicrobial compounds in addition to appropriate immune system development. However, we do not know how Staphylococcus spp adhere to skin. This application hypothesizes that species of staphylococci that colonize humans do so in a conserved manner via an Aap (or SasG in S. aureus) orthologue that binds corneocytes. Aap is a rod-like fibrillar protein that functions in initial adherence to corneocytes but also functions to mediate intercellular accumulation. To address this hypothesis, we have proposed the following specific aims: (1) understand the dynamics of Aap-mediated corneocyte adherence; (2) define the ligand specificity of Aap and SasG lectin domains and (3) investigate S. aureus SasG-dependent mechanisms of skin colonization. Overall, the proposed studies will address how staphylococci bind to skin, what ligand is bound, and thus could uncover new layers of crosstalk between pathogen and the host, potentially leading to novel therapeutic modalities for treating staphylococcal infections.