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：几十年来，呼吸道感染一直是全球死亡的三大主要原因之一。 新型高度传播性呼吸道病原体的出现以及当前的 SARS-CoV-2 和过去的流感大流行。当前的流感和 SARS-CoV-2 疫苗的重点是引发流感。 针对高度可变的病毒表面蛋白的抗体，需要频繁重新配制疫苗以匹配抗原性 不断进化的病毒株或变体逃避疫苗引发的抗体，因此，引发肺组织- 常驻记忆 T 细胞 (TRM) 能够识别跨病毒变体保守的表位，对于引发广泛的免疫反应至关重要 我们开发了基于组合佐剂的亚单位粘膜疫苗制剂，可引起抗病毒免疫。 异常强大且功能多样的肺/气道 CD8 和 CD4 TRM，并提供有效和广泛的 然而，对无特定病原体（SPF）小鼠的甲型流感病毒（IAV）和 SARS-CoV-2 的保护作用是一个核心。 问题是 SPF 小鼠的疫苗功效研究是否可以转化为人类，因为人类暴露于不同的环境中 近年来，脏小鼠（SPF 小鼠与宠物店小鼠共养）已被用来模拟人类。 值得注意的是，脏小鼠中的 TRM 数量大大增加，但其潜在机制是 我们有令人兴奋的初步数据表明，脏小鼠的肺和脾脏的数量显着增加。 具有转录属性的颗粒酶 BHI/CD44HI CD8 T 细胞 (T-betLO/EOMESLO/TCF-1LO) 提醒前体 TRM，为 TRM 细胞命运做好准备，首要目标是利用我们组合的高分辨率。 基于佐剂的疫苗方法和脏小鼠模型，以阐明不同微生物暴露对 前 TRM 的开发及其随后分化为可防御呼吸道病毒的 TRM。 目标 1 将检验以下假设：不同的微生物暴露会影响肺的发育和保护功能 针对 IAV 和 SARS-CoV-2 的 TRM 在这里，我们将比较肺 TRM 的发育和转录编程。 由两种联合佐剂疫苗制剂诱导，以及 SPF 和 SPF 中对 IAV 和 SARS-CoV-2 的保护性免疫 肮脏的老鼠。特定目标 2 将测试以下假设：接触不同的微生物会促进条件反射。 循环/淋巴前 TRM，导致接种 Dirty 小鼠肺部 TRM 分化增强。 和 SPF 小鼠，我们将深入剖析微生物暴露是否会增强幼稚 CD8 的预处理 或疫苗接种前的CD4 T细胞和/或疫苗接种期间抗原激活的效应T细胞，以决定TRM细胞的命运。 影响：拟议的研究将利用微生物暴露来提高小鼠模型预测人类的严谨性。 对疫苗的免疫反应，并为特定条件下肺部 TRM 的发展提供机制见解 因此，这种探索性的“高回报”R21 应用融合了意义和创新。 为进一步的机械研究奠定概念框架，为开发 生物学相关且可转化的临床前动物模型，以了解我们如何利用微生物群来增强疫苗- 诱导 T 细胞对 IAV 和 SARS-CoV-2 产生免疫力，这两种病毒对公共卫生具有重要意义。