Skin microbiome interactions with complement

 描述(申请人提供)：皮肤中含有多种微生物区系，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病中得到了很好的认识。然而，关于宿主对皮肤微生物区系的调节，以及微生物对宿主皮肤免疫的调节，人们知之甚少。我们之前已经证明，干扰补体信号会改变皮肤微生物区系的多样性和组成，同时改变皮肤炎症环境。此外，我们的RNA-SEQ研究表明，与补体信号和激活相关的基因在常规培养的小鼠皮肤中上调，表明共生微生物区系调节它们的表达。我们的主要假设是，皮肤微生物区系和补体之间存在机械联系。我们假设皮肤微生物区系是由补体塑造和维持的，反过来，共生微生物区系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)确定共生菌和病原体如何差异地诱导皮肤中补体基因的表达。我们还将确定在皮肤和软组织感染模型中，共生微生物区系重建是否可以调节补体基因的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，在小鼠模型中，补体缺乏在转移定植微生物区系的同时加速了切除伤口的愈合，我们将测试微生物在这一表型中的必要性和充分性。拟议研究的完成将填补我们对皮肤-微生物相互作用的基础知识的空白，即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区系在 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.