Mechanisms of STING-associated immunodeficiency

项目摘要 这项建议的目的是定义由刺痛功能获得所引起的免疫缺陷的机制。 小鼠的基因突变。STING是病毒和宿主DNA的胞液传感器。在检测到以下情况时启动STING 胞浆DNA触发抗病毒干扰素刺激基因(ISGs)的上调。常染色体显性 刺痛功能获得突变导致婴儿起病的刺痛相关血管病变， 风湿性疾病以血管病变、皮肤损害、间质性肺病和血管内皮生长因子上调为特征的风湿病 I型干扰素和免疫球蛋白。我们之前描述了一种SAVI(杂合子刺痛N153S小鼠)小鼠模型 表现出与SAVI患者的一些相似之处，但也有一些重要的区别。这些差异中的一些 可能是由于刺痛N153S小鼠被饲养在无病原体的环境中。虽然刺痛 检测病原体和共生微生物，病毒和微生物是否有助于刺痛 功能性疾病的发病机制以前还没有得到过检验。 出乎意料的是，我们发现刺痛功能获得突变小鼠不能形成淋巴结和Peyer‘s 补丁，表现出受损的抗原特异性CD8+T细胞反应，并严重容易感染。我们 将我们的STINN153S小鼠与缺乏STING上游调控因子和下游效应子的小鼠进行了杂交，因为 以及RoRγt-gfp小鼠。此外，我们正在培育启动子中带有牙线停止的刺痛N153S小鼠。 这将使我们能够确定STINN153S对淋巴组织器官发生的细胞类型特异性影响 (目标1)。由于STINN153S小鼠极易受到感染，我们将定义 病毒发病机制研究中的免疫缺陷，包括骨髓嵌合小鼠的研究以及 Rag1-/-和Rag1-/-stingN153S小鼠过继转移研究此外，我们还将测试野生型 SING N153S受体动物骨髓移植延长存活时间并防止自发性 老年小鼠的疾病和死亡(目标2)。最后，我们将确定环二核苷酸是否来自 刺痛N153S小鼠自发性疾病需要宿主(CGAMP)或共生微生物(c-di-GMP)。 (目标3)。总的来说，这些拟议的研究将定义发育缺陷和刺痛的方式- 介导的环二核苷酸检测可能导致免疫缺陷和自发性疾病 发病机制与刺痛功能获得有关。

Project Abstract The goal of this proposal is to define the mechanisms of immunodeficiency caused by a STING gain-of-function mutation in mice. STING is a cytosolic sensor of viral and host DNA. Activation of STING upon detection of cytosolic DNA triggers up-regulation of antiviral interferon (IFN)-stimulated genes (ISGs). Autosomal dominant STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI), a rheumatic disease characterized by vasculopathy, skin lesions, interstitial lung disease, and up-regulation of type I IFN and ISGs. We previously described a mouse model of SAVI (heterozygous STING N153S mice) that exhibited some similarities to patients with SAVI, but also some important differences. Some of these differences may be due to the fact that the STING N153S mice are housed in a pathogen-free environment. Although STING detects pathogens and commensal microbes, whether viruses and microbes contribute to STING gain-of- function disease pathogenesis has not previously been tested. Unexpectedly, we discovered that STING gain-of-function mutant mice fail to develop lymph nodes and Peyer's patches, exhibit impaired antigen-specific CD8+ T cell responses, and are severely vulnerable to infections. We crossed our STING N153S mice to mice lacking an upstream regulator and downstream effectors of STING, as well as Rorγt-GFP mice. Additionally, we are generating STING N153S mice with a floxed-stop in the promoter. This will permit us to define the cell type-specific effects of STING N153S on lymphoid tissue organogenesis (Aim 1). Since STING N153S mice are severely vulnerable to infection, we will define mechanisms of immunodeficiency in studies of viral pathogenesis, including studies of bone marrow chimeric mice as well as adoptive transfer studies into Rag1-/- and Rag1-/- STING N153S mice. Additionally, we will test whether wild-type bone marrow transplantation into STING N153S recipient animals prolongs survival and prevents spontaneous disease and death in older adult mice (Aim 2). Finally, we will determine whether cyclic dinucleotides from the host (cGAMP) or commensal microbes (c-di-GMP) are required for spontaneous disease in STING N153S mice. (Aim 3). Collectively, these proposed studies will define ways in which developmental defects and STING- mediated detection of cyclic dinucleotides may contribute to immunodeficiency and spontaneous disease pathogenesis associated with STING gain-of-function.