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Mechanisms of STING-associated immunodeficiency

STING 相关免疫缺陷的机制

基本信息

批准号：
10117178
负责人：
Jonathan J Miner
金额：
$ 8.18万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117178
关键词：
Adoptive Transfer Adult Affect American Animals Antibiotics Antibody Response Antigens Antiviral Agents Apoptosis Astrovirus Autoimmune Diseases Autoimmunity B-Lymphocytes Bacteria Biological Assay Bone Marrow Bone Marrow Transplantation CD8-Positive T-Lymphocytes Cell physiology Cells Cessation of life Chronic Control Animal DNA Data Defect Detection Development Dinucleoside Phosphates Disease Elderly Environment Enzymes Exhibits Fetus Flow Cytometry Genes Genetic Germ-Free Goals Helper-Inducer T-Lymphocyte Hematopoietic Histologic House mice Human Immune response Immunohistochemistry Immunologic Deficiency Syndromes Immunologics Impairment In Vitro Infection Interferon Type I Interferons Interstitial Lung Diseases Knockout Mice LoxP-flanked allele Lung Lung diseases Lymphoid Tissue Measures Mediating Microbe Mus Mutant Strains Mice Mutation Opportunistic Infections Organ Organogenesis Pathogenesis Patients Peptides Periodicity Peyer&apos s Patches Predisposition Production Quantitative Reverse Transcriptase PCR RNA Rag1 Mouse Rare Diseases Rheumatism Role Second Messenger Systems Signal Transduction Stimulator of Interferon Genes Sting Injury T cell response T-Cell Proliferation T-Lymphocyte Techniques Testing Tumor Necrosis Factor-Beta Up-Regulation Vascular Diseases Viral Viral Pathogenesis Virus Virus Diseases West Nile virus antigen-specific T cells autoinflammatory base cell type commensal bacteria commensal microbes congenital immunodeficiency cytokine defined contribution detector disease-causing mutation fetal gain of function gain of function mutation gammaherpesvirus germ free condition gut microbes infancy lung development lymph nodes lymphotoxin beta receptor microbial mouse model neutralizing antibody pathogen prevent promoter receptor response sensor skin disorder skin lesion tertiary lymphoid organ viral DNA

项目摘要

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.

项目摘要该提案的目标是定义由 STING 功能获得引起的免疫缺陷的机制小鼠的突变。 STING 是病毒和宿主 DNA 的胞质传感器。检测到时激活 STING 胞质 DNA 触发抗病毒干扰素 (IFN) 刺激基因 (ISG) 的上调。常染色体显性遗传 STING 功能获得性突变会导致婴儿期发病的 STING 相关血管病变 (SAVI)，这是一种以血管病变、皮肤病变、间质性肺疾病和 I 型干扰素和 ISG。我们之前描述了 SAVI 小鼠模型（杂合 STING N153S 小鼠）与 SAVI 患者表现出一些相似之处，但也存在一些重要的差异。其中一些差异可能是由于 STING N153S 小鼠饲养在无病原体的环境中。虽然STING 检测病原体和共生微生物，病毒和微生物是否有助于 STING 增益- 功能性疾病的发病机制以前尚未被测试过。出乎意料的是，我们发现STING功能获得性突变小鼠无法发育淋巴结和派尔氏淋巴结斑块，表现出受损的抗原特异性 CD8+ T 细胞反应，并且非常容易受到感染。我们将我们的 STING N153S 小鼠与缺乏 STING 上游调节器和下游效应器的小鼠进行杂交，如以及 Rorγt-GFP 小鼠。此外，我们正在生成启动子中带有 floxed-stop 的 STING N153S 小鼠。这将使我们能够定义 STING N153S 对淋巴组织器官发生的细胞类型特异性影响（目标 1）。由于 STING N153S 小鼠非常容易受到感染，我们将定义其机制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对 Rag1-/- 和 Rag1-/- STING N153S 小鼠的过继转移研究。此外，我们将测试野生型是否骨髓移植到 STING N153S 受体动物中可延长生存期并预防自发性老年小鼠的疾病和死亡（目标 2）。最后，我们将确定环状二核苷酸是否来自 STING 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 STING 的方式：环状二核苷酸介导的检测可能导致免疫缺陷和自发性疾病与 STING 功能获得相关的发病机制。