Vaccine-Induced Mucosal T-Cell Immunity to Respiratory Viruses in Dirty Mice

疫苗诱导脏小鼠粘膜 T 细胞对呼吸道病毒的免疫

• 批准号: 10746925
• 负责人: Marulasiddappa Suresh
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746925
• 关键词: 2019-nCoV; Adjuvant; Agonist; Animal Model; Antibodies; Antigens; Biomedical Research; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 vaccine; Cell Count; Cells; Cessation of life; Communicable Diseases; Cytoprotection; Data; Development; Epithelium; Epitopes; Exposure to; Formulation; Genetic; Genetic Transcription; Goals; Granzyme; Growth; Hemagglutinin; Human; Immune response; Immunity; Immunologics; Inbred Mouse; Inbreeding; Infection; Influenza; Influenza A virus; Intranasal Administration; Investigation; Learning; Link; Lipid A; Lung; Lymphoid; Membrane Proteins; Memory; Microbe; Molecular; Mucous Membrane; Mus; Mutation; Neuraminidase; Nucleoproteins; Proteins; Public Health; Research; Resolution; Respiratory System; Respiratory Tract Infections; Seasons; Seminal; Site; Spleen; Structure of parenchyma of lung; Subunit Vaccines; Surface; T cell response; T-Lymphocyte; TLR4 gene; Testing; Time; Tissue Differentiation; Tissues; Translating; Vaccinated; Vaccination; Vaccine Research; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus Diseases; Work; antiviral immunity; clinical practice; conditioning; effector T cell; efficacy study; experience; germ free condition; human model; human pathogen; immune system function; improved; influenza A virus nucleoprotein; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; insight; interest; microbial; microbial community; microbiome composition; microbiota; mouse model; mucosal vaccine; nanoemulsion; novel; pandemic influenza; pre-clinical; preconditioning; protective efficacy; pulmonary function; respiratory pathogen; respiratory virus; response; tissue resident memory T cell; vaccine development; vaccine efficacy; vaccine formulation

Abstract: Respiratory infections have been among the top three leading causes of global deaths for decades. Their importance is reinforced by the emergence of novel highly transmissible respiratory pathogens, as witnessed in the current SARS-CoV-2 and past influenza pandemics. Current influenza and SARS-CoV-2 vaccines are focused on eliciting antibodies to highly mutable viral surface proteins, and frequent vaccine reformulations are needed to match the antigenicity of constantly evolving viral strains or variants that evade vaccine-elicited antibodies. Therefore, elicitation of lung tissue- resident memory T cells (TRMs), which recognize epitopes that are conserved across viral variants is critical to elicit broad anti-viral immunity. We have developed combination adjuvant-based subunit mucosal vaccine formulations that elicit exceptionally strong and functionally diverse lung/airway CD8 and CD4 TRMs and provide effective and broad protection against influenza A virus (IAV) and SARS-CoV-2 in specific-pathogen-free (SPF) mice. However, a central question is whether vaccine efficacy studies in SPF mice are translatable to humans, who are exposed to diverse microbial species. In recent years, Dirty mice (SPF mice cohoused with pet store mice), have been used to model human immune responses. Significantly, TRM numbers are greatly increased in Dirty mice, but the underlying mechanisms are unknown. We have exciting preliminary data that the lungs and spleen of Dirty mice have markedly elevated number of Granzyme BHI/CD44HI CD8 T cells with transcriptional attributes (T-betLO/EOMESLO/TCF-1LO) reminiscent of precursor TRMs, which are poised for a TRM cell fate. The overarching goal is to exploit the high resolution of our combination adjuvant-based vaccine approach and the Dirty mouse model to elucidate the effects of diverse microbial exposure on the development of pre-TRMs and their subsequent differentiation into TRMs that protect against respiratory viruses. Specific Aim 1 will test the hypothesis that diverse microbial exposure influences the development and protective functions of lung TRMs against IAV and SARS-CoV-2. Here, we will compare the development and transcriptional programming of lung TRMs induced by two combination adjuvant vaccine formulations and protective immunity to IAV and SARS-CoV-2 in SPF and Dirty mice. Specific Aim 2 will test the hypothesis that diverse microbial exposure promotes the conditioning of circulating/lymphoid pre-TRMs, leading to enhanced differentiation of TRMs in lungs of vaccinated Dirty mice. Here, in Dirty and SPF mice, we will incisively dissect whether diverse microbial exposure enhances the pre-conditioning of naïve CD8 or CD4 T cells prior to vaccination and/or antigen-activated effector T cells during vaccination, to a TRM cell fate. Impact:. Proposed studies will leverage microbial exposure to improve the rigor of mouse models to predict human immune response to vaccines, and provide mechanistic insights into the development of TRMs in the lung under conditions of diverse microbial exposure. Hence, this exploratory ‘high pay off’ R21 application blends significance and innovation to lay the conceptual framework for further mechanistic investigations that will pave the way for the development of a biologically relevant and translatable pre-clinical animal model to learn how we can leverage microbiota to enhance vaccine- induced T-cell immunity to IAV and SARS-CoV-2, which are human respiratory viruses of public health importance.

摘要：数十年来，呼吸道感染一直是全球死亡的主要三大原因之一。他们的 正如当前所见，新型高度可传播的呼吸病原体的出现增强 SARS-COV-2和过去会影响大流行。当前的影响和SARS-COV-2疫苗集中于引起 高度可变病毒表面蛋白的抗体，以及经常需要疫苗改革以匹配抗原性 不断发展的病毒株或逃避疫苗吸引抗体的变体。因此，肺组织的诱导 识别在病毒变异中保守的表位的居民记忆T细胞（TRM）对于引起广泛的范围至关重要 抗病毒免疫。我们已经开发了引起的基于调整的基于调整的亚基粘膜疫苗配方 异常强大且功能多样的肺/气道CD8和CD4 TRM，并提供有效且广泛的 防止特异性无性病原体（SPF）小鼠中的影响力A病毒（IAV）和SARS-COV-2的保护。但是，一个中央 问题是SPF小鼠中的疫苗效率研究是否可以翻译成接触潜水员的人类 微生物物种。近年来，肮脏的小鼠（SPF小鼠与宠物店小鼠共同）已被用来建模人类 免疫反应。值得注意的是，肮脏的小鼠中TRM数量大大增加，但潜在的机制是 未知。我们有令人兴奋的初步数据，即脏老鼠的肺和脾脏显着增加 具有转录属性（t-betlo/eomeslo/tcf-1lo）的粒酶BHI/CD44HI CD8 T细胞让人联想到前体 TRM，为TRM细胞命运中毒。总体目标是利用我们组合的高分辨率 基于佐剂的疫苗方法和肮脏的小鼠模型，以阐明潜水员微生物暴露对 TRM前的发展及其随后的分化为防止呼吸病毒的TRM。具体的 AIM 1将检验以下假设：潜水微生物暴露会影响肺的发育和保护功能 对IAV和SARS-COV-2的TRM。在这里，我们将比较肺TRM的开发和转录编程 由两个组合诱导的疫苗公式，并保护对IAV和SARS-COV-2的免疫力 肮脏的老鼠。具体目标2将检验以下假设：潜水员微生物暴露促进了条件 循环/淋巴样前TRM，导致疫苗接种脏小鼠肺中TRM的分化增强。在这里，肮脏 和SPF小鼠，我们将敏锐地剖析潜水员微生物的暴露是否增强了幼稚的CD8的预先调节 或在真空吸尘器上进行真空和/或抗原激活的效应T细胞之前的CD4 T细胞，直至TRM细胞命运。 影响：。拟议的研究将利用微生物的暴露来改善小鼠模型的严格性来预测人类 对疫苗的免疫反应，并在条件下对肺中TRM的发展提供机械见解 潜水员微生物的暴露。因此，这种探索性的“高薪” R21应用程序融合了意义和创新 为进一步的机械投资奠定概念框架，这将为开发的发展铺平道路 生物学相关且可翻译的临床前动物模型，以了解我们如何利用微生物群来增强疫苗 引起对IAV和SARS-COV-2的T细胞免疫，这是人类呼吸道重要的重要性。