Respiratory mucosal immune development in early life and the quest for protective local memory against respiratory syncytial virus.

生命早期呼吸道粘膜免疫发育以及针对呼吸道合胞病毒的保护性局部记忆的探索。

• 批准号: 10161729
• 负责人: Allison Marie Wahl Malloy
• 金额: $ 45.16万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161729
• 关键词: 2 year old; Address; Adult; Age; Aging; Agonist; Antigen-Presenting Cells; Antigens; CD8-Positive T-Lymphocytes; Cause of Death; Cells; Child; Complex; Cues; Cytolysis; Dendritic Cells; Development; Disease; Epithelial Cells; Epitopes; Formalin; Genetic Transcription; Goals; Hospitalization; Host Defense; Human; Immune; Immune Targeting; Immunity; Immunization; Impairment; Infant; Infection; Influenza; Innate Immune Response; Interferon Type I; Life; Location; Lower respiratory tract structure; Lung; Malaria; Measures; Memory; Monoclonal Antibodies; Mucosal Immune Responses; Mucous Membrane; Mus; Neonatal; Play; Predisposition; Primary Infection; Prophylactic treatment; Proteins; Research; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Respiratory syncytial virus; Role; Site; Structure of parenchyma of lung; Surface; T cell differentiation; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Toll-like receptors; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Virus; Virus Diseases; Vulnerable Populations; adaptive immunity; age related; design; experience; immune activation; immunoregulation; improved; infant death; innovation; mouse model; neonate; novel; pathogen; respiratory pathogen; respiratory virus; response; symptomatology

PROJECT SUMMARY Globally, respiratory syncytial virus (RSV) is the single most important pathogen causing lower respiratory tract disease in the first year of life, and for which there is no vaccine. Previous vaccine strategies resulted in severe RSV disease in infant vaccine recipients upon primary infection. Over the past 60 years subsequent vaccines have failed. We, therefore, developed a neonatal murine model of RSV to interrogate the respiratory mucosal immune response against RSV. Our overarching goal is to identify age-dependent immune regulation of mucosal adaptive immune cells that results in susceptibility to RSV and can be targeted to precisely design vaccines for infants. Tissue-resident memory T cells have recently been discovered to provide sterilizing protection against influenza by rapidly responding to infection. CD8 T cells are critical for RSV clearance in murine models and are associated with reduction of virus and reduced symptomatology in humans. Our research and that of other show that neonatal CD8 T cell responses are often reduced compared to adults and poorly differentiate into memory cells. How RSV-specific tissue-resident memory T cells (TRM) develop in infants and if they can be induced to provide protection is unknown. Prior vaccines have not targeted this newly discovered T cell subset and they have not been explored for vaccine design. Our central hypothesis to be tested is that neonatal RSV-specific T cells poorly differentiate into TRM resulting in poor protective immunity, but that enhancing innate immune activation can improve neonatal RSV-specific T cell localization to the respiratory mucosa and establish protective RSV-specific TRM. Three Specific Aims are proposed to test this hypothesis, with the goal of identifying novel immune targets for RSV vaccines designed for neonates. The proposed innovative experimental approaches are designed to: (1) identify the requirements of the neonatal innate immune response to provide antigen and/or T cell activation to establish RSV-specific TRM, (2) identify the subspecialized antigen presenting cells that induce RSV-specific TRM and how to enhance APC activation to retain RSV-specific memory CD8 T cells in the respiratory mucosa, (3) define the role of RSV-epitope specific TRM to protect against RSV infection. These studies will define the key components of vaccine design including antigen availability and the critical antigen presenting cells to target in order to develop RSV-specific TRM in neonates that protect upon challenge.

项目总结