Harnessing ZBP1-driven cell death to improve influenza vaccine efficacy

利用 ZBP1 驱动的细胞死亡来提高流感疫苗的功效

基本信息

批准号：
10455196
负责人：
SIDDHARTH BALACHANDRAN
金额：
$ 84.79万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-13 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455196
关键词：
Adjuvant Adopted Agonist Antigens Apoptosis Attenuated Vaccines CD8-Positive T-Lymphocytes Cell Death Cell Death Signaling Process Cell Nucleus Cells Cellular Immunity Cessation of life Cues Cytoplasm Cytotoxic T-Lymphocytes Defective Viruses Double-Stranded RNA Engineering Epithelial Cells Extracellular Space Goals Hand Hospitalization Host Defense Humoral Immunities Immune Immune response Immunity Immunologics Individual Inflammatory Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Left Ligands Lung Lytic Virus Mediating Modality Modeling Molecular Conformation Necrosis Nuclear Nuclear Envelope Nucleoproteins Pathogenesis Pathologic Pathway interactions Positioning Attribute Proteins RNA RNA Sequences Recombinants Reporting Role Rupture Signal Pathway Source Stromal Cells Structure T cell response T-Lymphocyte Technology Testing Vaccination Vaccines Viral Antigens Viral Genome Viral Proteins Virus Virus Diseases Virus Replication adaptive immune response adaptive immunity airway epithelium anti-influenza base cell type cytotoxic CD8 T cells design experimental study genomic RNA immunogenic immunogenic cell death improved in vivo influenza virus vaccine lymph nodes macrophage neutrophil next generation novel strategies novel vaccines prevent response seasonal influenza sensor universal influenza vaccine vaccine efficacy vaccine response

项目摘要

Project Summary Vaccination represents the most effective means of preventing influenza A virus (IAV) infections. Current approaches to IAV vaccines primarily target the HA protein, but HA undergoes significant antigenic drift and is thus a poor target for lasting humoral immunity. An alternative approach to developing a universal IAV vaccine is to target internal viral proteins (such as the nucleoprotein), which are also highly conserved between most IAV strains. A major roadblock to this approach, however, is a lack of adjuvants that trigger the right kind of immune response - a ‘type I’ (or Th1/CD8+ T-cell driven) response - to these internal antigens. In this proposal, we outline a new strategy that seeks to harness immunogenic cell death as a means of activating type I immunity to IAV vaccines. We have identified a host signaling pathway which accounts for almost all IAV-activated immunogenic death in infected cells, including primary airway epithelial cells, macrophages and DCs. This cell death pathway is initiated when the host sensor protein ZBP1 detects IAV genomic RNA and activates parallel pathways of programmed necrosis (necroptosis) and apoptosis to kill the infected cell and instigate CD8+ T cell-mediated adaptive immune responses. Adding to the attractiveness of ZBP1-initiated cell death as a vaccine approach are our discoveries, first, that IAV produces a new form of double-stranded RNA - termed Z-RNA - to activate ZBP1. Z-RNA is thus a new PAMP, and can be readily harnessed to trigger immunogenic cell death and adjuvant IAV vaccines. Second, ZBP1 initiates necroptosis from the nucleus, resulting in nuclear envelope rupture and release of highly-immunogenic nuclear DAMPs and IAV antigens. Nuclear necroptosis is even more immunogenic than conventional (cytoplasm-initiated) necroptosis. As ZBP1-driven immunogenic cell death (both apoptosis and nuclear necroptosis) is important for effective anti-IAV cytotoxic T cell responses, our discoveries allow us to propose that Z-RNAs are potent new adjuvants for activating type I immune responses to IAV, and that recombinant IAVs engineered to produce Z-RNAs represent new type I immunity-activating vaccines. In this proposal, three labs with strong expertise in IAV cell death signaling (Balachandran), recombinant IAV technology (Langlois), and pathogenesis/vaccine strategies (Lopez) will unite to identify IAV-generated Z-RNAs that activate ZBP1 (Aim 1); determine which stromal and immune cell types die by ZBP1-mediated mechanisms to initiate and regulate effective adaptive immune responses (Aim 2); and test if triggering ZBP1-mediated cell death with synthetic and virus-generated Z-RNAs can be leveraged to inform and supply next-generation vaccines capable of providing effective cross-protective immunity to IAV (Aim 3).

项目摘要疫苗接种最有效的病毒（IAV）感染。 IAV疫苗主要目标HA蛋白的方法，但HA经历了明显的抗原漂移，并且是IS是IS是IS IS IS ISS。因此，持久的体液免疫的目标很差。是靶向内部病毒蛋白（例如核蛋白），在这里，大多数IAV也很高菌株。响应-a'类型I'（或TH1/CD8+ T -CELL驱动）响应 - 在此提案中，我们概述了这些抗原。一种新的策略，试图利用免疫原性死亡，因为激活I型免疫对IAV 疫苗我们已经确定了几乎所有IAV活化的免疫原性的宿主信号通路感染细胞的死亡，包括原代气道上皮细胞，巨噬细胞和DC。当宿主传感器蛋白ZBP1检测IAV基因组RNA和激活途径时，开始编程坏死（坏死tostosis）和凋亡杀死感染细胞并介入CD8+ T细胞介导自适应免疫反应。首先，我们发现IAV产生了一种新形式的双链RNA termed z -RNA-激活ZBP1。因此，Z-RNA是一种新的弹药疫苗。高度免疫原性核潮湿和IAV抗原。常规（细胞质的）坏死性。细胞核坏死tostosis）对于有效的抗IAV细胞毒性T细胞反应很重要，我们的发现使我们能够提出Z-RNA是激活I类型的有效新佐剂，对IAV有所反应，并且重组IAV在此中产生Z-RNA抑制作用的Z-RNA抑制作用提案，三个在IAV细胞死亡信号传导（Balachandran），重组IAV方面具有强大专业知识的实验室技术（Langlois）和发病机理/疫苗策略（Lopez）将团结成IAV生成的Z-RNA 激活ZBP1（AIM 1）； initiale和常规的有效自适应免疫疗法（AIM 2）；可以利用合成和病毒生成的Z-RNA的死亡来供应下一代能够提供有效跨保护IAV的疫苗（AIM 3）。