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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：
10571901
负责人：
Jonathan J Miner
金额：
$ 55.44万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2024-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571901
关键词：
Adoptive Transfer Adult Affect American Animals Antibiotics Antibody Response Antigens Apoptosis Astrovirus Autoimmune Diseases Autoimmunity B-Lymphocytes Bacteria Biological Assay Bone Marrow Bone Marrow Transplantation CD8-Positive T-Lymphocytes Cell Survival 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 Heterozygote 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 NF-kappa B Opportunistic Infections Organ Organogenesis Pathogen detection 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 Tissues Tumor Necrosis Factor-Beta Up-Regulation Vascular Diseases Viral Viral Pathogenesis Virus Virus Diseases West Nile virus antigen-specific T cells autoinflammatory diseases autosome 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