Impact of Resident Memory CD8 T Cells on Respiratory Virus Transmission

常驻记忆 CD8 T 细胞对呼吸道病毒传播的影响

• 批准号: 10679458
• 负责人: SARAH MICHALETS
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679458
• 关键词: Address; Adenovirus Vector; Anatomy; Animal Model; Antibodies; Antigens; Area; Attenuated; B-Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cellular Immunity; Data; Disease Outbreaks; Disease Progression; Effectiveness; Epithelial Cells; Epitopes; Event; Ferrets; Flow Cytometry; Future; Genes; Health; Hemagglutinin; Human; Humoral Immunities; IFNGR1 gene; Immune; Immune response; Immunity; Immunize; Immunologics; Infection; Infection prevention; Influenza; Interferon Type II; Knockout Mice; Knowledge; Longevity; Lower respiratory tract structure; LoxP-flanked allele; Luciferases; Lung; Mediating; Memory; Modeling; Mucous Membrane; Mus; Nasal Epithelium; Nasal cavity; Outcome; Pathway interactions; Population; Production; Productivity; Proteins; Reagent; Recombinants; Reporter; Respiration; Respiratory System; Role; Sendai virus; Signal Transduction; Site; Stains; Surface; Surveys; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Epitopes; Time; Upper respiratory tract; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Genes; Virus; Virus Diseases; Virus Replication; airway epithelium; cytokine; design; guinea pig model; imaging study; in vivo; in vivo imaging; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; insight; mouse model; new pandemic; novel; pandemic potential; parainfluenza virus; pathogen; prevent; respiratory; respiratory infection virus; respiratory virus; response; seasonal influenza; single-cell RNA sequencing; tissue resident memory T cell; transcriptome sequencing; transmission process; vaccination strategy; vaccine development; viral transmission

PROJECT SUMMARY/ABSTRACT Intranasal vaccination and respiratory virus infection induces populations of antigen specific B cells and T cells in mucosal tissues. The resulting memory T cells recognize internal epitopes that are conserved across viral strains and can provide protection against antigenically novel, potentially pandemic variants. One subset of memory T cells includes tissue resident memory T cells (TRM) which are poised to provide rapid immune responses at the site of pathogen entry. Numerous studies using direct intranasal inoculation have demonstrated that CD8 TRM in the respiratory tract can mediate protection against heterosubtypic influenza strains. However, the ability of CD8 TRM to limit natural respiratory virus transmission has not been defined. Because murine adapted influenza viruses do not readily transmit between mice and immunological reagents for ferret and guinea pig models are limited, studying the immunological mechanisms behind transmission has been significantly hindered. To bridge this gap in knowledge, we developed a murine model using Sendai virus, a mouse parainfluenza virus which naturally transmits between mice. Through the use of a Luciferase encoding Sendai virus, transmission dynamics can be evaluated by in vivo imaging. Our preliminary data demonstrates that Sendai virus specific CD8 TRM in the respiratory tract limit transmission of Sendai virus to immunized contacts. We seek to further define the mechanisms underlying this TRM mediated protection against transmission by evaluating relative contributions of TRM in different anatomical compartments of the respiratory tract. Because studies have demonstrated that a decline in lung and airway TRM corresponds to a loss of heterosubtypic immunity, we will evaluate the durability of TRM mediated protection following various vaccination strategies. Furthermore, we will investigate the TRM antiviral mechanisms that limit transmission with a focus on cytokines and cytolytic proteins. Understanding cellular immune mechanisms in respiratory virus transmission will impact future vaccine development designed to prevent respiratory virus outbreaks.

项目总结/摘要 鼻内接种和呼吸道病毒感染诱导抗原特异性B细胞和T细胞群体 在粘膜组织中。由此产生的记忆T细胞识别跨病毒保守的内部表位， 菌株，并可以提供针对抗原性新的、潜在的大流行性变体的保护。的一个子集 记忆T细胞包括组织驻留记忆T细胞（TRM），其准备提供快速免疫应答。 病原体进入部位的反应。许多使用直接鼻内接种的研究已经证明 呼吸道中的CD 8 TRM可以介导针对异亚型流感病毒株的保护。然而，在这方面， CD 8 TRM限制自然呼吸道病毒传播的能力尚未确定。因为鼠科 适应性流感病毒不易在小鼠与雪貂和豚鼠免疫试剂之间传播 猪模型有限，研究传播背后的免疫机制已显着 受限为了弥合这一知识差距，我们开发了一种使用仙台病毒的小鼠模型， 副流感病毒在小鼠之间自然传播。通过使用编码仙台的荧光素酶 病毒，传播动力学可以通过体内成像来评估。我们的初步数据表明， 呼吸道中仙台病毒特异性CD 8 TRM限制仙台病毒向免疫接触者的传播。 我们试图通过以下方法进一步确定TRM介导的抗传播保护的机制： 评估TRM在呼吸道不同解剖学隔室中的相对贡献。因为 研究表明，肺和气道TRM的下降对应于异亚型TRM的丧失， 为了提高免疫力，我们将评估各种疫苗接种策略后TRM介导的保护的持久性。 此外，我们将研究TRM的抗病毒机制，限制重点细胞因子的传播 和溶细胞蛋白。了解呼吸道病毒传播中的细胞免疫机制将影响 未来的疫苗开发旨在预防呼吸道病毒爆发。