Skin microbiome interactions with complement

 描述（由申请人提供）：皮肤含有多种微生物群，对皮肤健康和疾病具有重要作用。宿主-微生物相互作用的作用在多种皮肤疾病中得到了很好的理解。然而，关于宿主对皮肤微生物群的调节和宿主皮肤免疫的微生物调节知之甚少。我们之前已经表明，破坏补体信号传导改变了皮肤微生物群的多样性和组成，同时改变了皮肤炎症环境。此外，我们的RNA-seq研究表明，与无菌小鼠皮肤相比，与补体信号传导和激活相关的基因在常规饲养的小鼠皮肤中上调，表明肠道微生物群调节其表达。我们的首要假设是，皮肤微生物群和补体之间存在机械联系。我们认为皮肤微生物群是由补体形成和维持的，相反，皮肤微生物群在基因表达水平上调节补体。为了验证我们的假设，我们提出了以下目标：1）确定细菌和病原体如何差异诱导皮肤中的补体基因表达。我们还将确定在皮肤和软组织感染模型中，肠道微生物群重建是否可以调节补体基因表达并改善感染结果。2)建立影响皮肤微生物组成、多样性和数量的补体效应途径。根据初步数据表明，补体缺乏加速小鼠模型中的切除伤口愈合，同时转移定植微生物群，我们将测试微生物群在这种表型中的必要性和充分性。完成拟议的研究将填补我们对皮肤-微生物相互作用的基础知识的空白，破坏这些相互作用的功能后果，同时促进未来关于皮肤微生物群在皮肤疾病中的作用的研究问题。 疾病、伤口愈合和感染。

 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.