Abstract: Staphylococcus aureus infections have emerged as a major source of morbidity and mortality in the United States and across the globe. The high virulence potential associated with certain S. aureus lineages combined with the evolution of multidrug-resistance exacerbate this healthcare crisis. In spite of impressive advances in public health, clinical science and medical care, new therapeutic agents effective against Methicillin-Resistant S. aureus (MRSA) are limited. Mice are the most commonly utilize animal models for studying S. aureus pathogenesis and we have learned a great deal about the host response to MRSA infections. However, many S. aureus virulence factors are human specific and numerous aspects of the murine host response fail to mimic that of the human. This failure of murine models to recapitulate human host response to S. aureus as manifested in the failure of several promising immune modulators in murine studies to translate to humans. Consequently, there is an urgent need for small animal models to understand pathogenesis and the human immune response as well as to develop effective therapeutics. This application proposes to develop an improved humanized mouse model for S. aureus SSTIs that entails the grafting of full-thickness human skin onto immuno-humanized animals carrying autologous human immune cells and lymphoid tissues. This will allow for intradermal inoculation into human skin, a significant improvement to current models. Furthermore, this proposal seeks to expand our knowledge of the temporal and malleable murine host response to S. aureus SSTIs into that of humans. This collaboration will result in the innovative development of novel in vivo model systems to understand the human host response to MRSA infections. Additionally, we will test whether new therapeutic strategies that modulate the murine host responses to hasten MRSA clearance are equally effective in humanized animals.