Skin microbiome interactions with complement

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 DESCRIPTION (provided by applicant): The skin harbors a diverse population of microbiota with important functions in cutaneous health and disease. The role of host-microbe interactions is well appreciated in multiple skin disorders. However, very little is known regarding host modulation of skin microbiota, and microbial regulation of host cutaneous immunity. We have previously shown that disrupting complement signaling alters the diversity and composition of skin microbiota in parallel with changing the cutaneous inflammatory milieu. Further, our RNA-seq studies indicate that genes related to complement signaling and activation are upregulated in conventionally raised mouse skin as compared to germ free mouse skin, suggesting that the commensal microbiota regulate their expression. Our overarching hypothesis is that there is a mechanistic link between the skin microbiota and complement. We posit that the skin microbiota are shaped and maintained by complement, and conversely, that the commensal microbiota modulate complement at the gene expression level. To test our hypothesis we propose the following aims: 1) Determine how commensals and pathogens differentially induce complement gene expression in skin. We will also determine if commensal microbiota reconstitution can tune complement gene expression and improve infection outcome in a model of skin and soft tissue infection. 2) Establish the complement effector pathways that impact cutaneous microbial composition, diversity, and quantity. Following up on preliminary data indicating that complement deficiency accelerates excisional wound healing in mouse models in parallel with shifting the colonizing microbiota, we will test the necessity and the sufficiency of the microbiot in this phenotype. Completion of the proposed studies will fill a gap in our fundamental knowledge of skin-microbe interactions, the functional consequences of disrupting these interactions, while facilitating future research questions regarding the role of skin microbiota in disease, wound healing, and infection.