Abstract:Staphylococcus aureus infections have emerged as a major source of morbidity and mortality in the UnitedStates and across the globe. The high virulence potential associated with certain S. aureus lineages combinedwith the evolution of multidrug-resistance exacerbate this healthcare crisis. In spite of impressive advances inpublic health, clinical science and medical care, new therapeutic agents effective against Methicillin-ResistantS. aureus (MRSA) are limited. Mice are the most commonly utilize animal models for studying S. aureuspathogenesis and we have learned a great deal about the host response to MRSA infections. However, manyS. aureus virulence factors are human specific and numerous aspects of the murine host response fail to mimicthat of the human. This failure of murine models to recapitulate human host response to S. aureus as manifestedin 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 responseas well as to develop effective therapeutics. This application proposes to develop an improved humanized mousemodel for S. aureus SSTIs that entails the grafting of full-thickness human skin onto immuno-humanized animalscarrying autologous human immune cells and lymphoid tissues. This will allow for intradermal inoculation intohuman skin, a significant improvement to current models. Furthermore, this proposal seeks to expand ourknowledge of the temporal and malleable murine host response to S. aureus SSTIs into that of humans. Thiscollaboration will result in the innovative development of novel in vivo model systems to understand the humanhost response to MRSA infections. Additionally, we will test whether new therapeutic strategies that modulatethe murine host responses to hasten MRSA clearance are equally effective in humanized animals.