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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要鼻内疫苗接种和呼吸道病毒感染诱导抗原特异性 B 细胞和 T 细胞群在粘膜组织中。由此产生的记忆 T 细胞可识别病毒中保守的内部表位菌株，并可以提供针对抗原性新颖、潜在大流行变种的保护。的一个子集记忆 T 细胞包括组织驻留记忆 T 细胞 (TRM)，可提供快速免疫病原体进入部位的反应。大量使用直接鼻内接种的研究表明呼吸道中的 CD8 TRM 可以介导针对异亚型流感病毒株的保护作用。然而， CD8 TRM 限制自然呼吸道病毒传播的能力尚未确定。因为鼠类适应的流感病毒不易在小鼠和雪貂和几内亚的免疫试剂之间传播猪模型有限，对传播背后的免疫机制的研究已取得显着进展阻碍。为了弥补这一知识差距，我们使用仙台病毒开发了一种小鼠模型，一种小鼠副流感病毒在小鼠之间自然传播。通过使用仙台萤光素酶编码病毒的传播动力学可以通过体内成像进行评估。我们的初步数据表明呼吸道中仙台病毒特异性 CD8 TRM 可限制仙台病毒向免疫接触者的传播。我们寻求进一步定义这种 TRM 介导的防止传播的机制：评估 TRM 在呼吸道不同解剖区室中的相对贡献。因为研究表明，肺和气道 TRM 的下降对应于异亚型的丧失免疫力，我们将评估采用各种疫苗接种策略后 TRM 介导的保护的持久性。此外，我们将研究限制传播的 TRM 抗病毒机制，重点关注细胞因子和溶细胞蛋白。了解呼吸道病毒传播中的细胞免疫机制将影响未来疫苗的开发旨在预防呼吸道病毒的爆发。