Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation

项目摘要 功能丧失突变和先天抗病毒蛋白的抑制，如OAS2和OASL，与高 老鼠和人类的病毒感染率。由于干扰素的诱导作用，这些抗病毒蛋白通常 称为干扰素刺激基因(ISG)。而重组干扰素刺激这些抗病毒药物的产生 蛋白质，I型干扰素的严重毒性是其治疗效果的主要限制因素。此外，药理学 抗病毒药物，如阿昔洛韦，在脆弱的患者中引发中性粒细胞减少和肾毒性的风险很高 人口。因此，临床上对新的抗病毒药物的需求还远远没有得到满足。这种需求可以是 通过发展对内源性抗病毒蛋白和干扰素非依赖性调节的全面了解来解决 通过激活这一令人难以置信的强大的天然抗病毒途径来确定治疗和预防的目标。我们的 所提出的工作将回答重要的问题：1)哪些干扰素不依赖的信号和途径可以诱导 抗病毒能力？2)上皮抗病毒先天免疫在单个细胞水平上是否不同？3)哪些因素 合作诱导先天抗病毒免疫？

Project Summary Loss-of-function mutations and suppression of innate antiviral proteins, such as OAS2 and OASL are associated with high viral infection rates in mice and humans. Because of their induction by interferons, these antiviral proteins are often referred to as interferon-stimulated genes (ISG). While recombinant interferon stimulates production of these antiviral proteins, type I interferon’s severe toxicity is the major limitation in its therapeutic utility. Additionally, pharmacological antivirals, such as acyclovir, have a high risk for triggering neutropenia and nephrotoxicity in vulnerable patient populations. Therefore, there is a significant unmet clinical need for new antiviral therapeutics. This need can be addressed by developing a full understanding of interferon-independent regulation of endogenous antiviral proteins and identifying targets for therapy and prevention by activation of this incredibly potent natural antiviral pathway. Our proposed work will answer important question: 1) Which interferon-independent signals and pathways can induce antiviral competence? 2) Does epithelial antiviral innate immunity differ on a single cell level? 3) What factors collaborate in the induction of innate antiviral immunity?