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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).

项目总结