Genetically modified pigs to model NKT cell immunity to influenza virus infection

转基因猪模拟 NKT 细胞对流感病毒感染的免疫

• 批准号: 10602471
• 负责人: John Driver
• 金额: $ 67.09万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602471
• 关键词: Address; Affect; Animal Model; Antigens; Cell Shape; Cell physiology; Cells; Cellular Immunity; Cytotoxic T-Lymphocytes; Dangerousness; Disease; Drug or chemical Tissue Distribution; Family suidae; Foundations; Frequencies; Funding Opportunities; Genes; Goals; Hemagglutinin; Host Defense; Human; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologic Memory; Immunologics; Infection; Inflammation; Influenza; Influenza A virus; Integration Host Factors; Knock-out; Knockout Mice; Knowledge; Lung; Lung diseases; Modeling; Mus; Natural Immunity; Organ; Peptides; Play; Population; Predisposition; Production; Property; Resistance; Respiratory Disease; Respiratory Tract Infections; Role; Shapes; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Vaccination; Vaccines; Viral Antigens; Virus; Virus Diseases; adaptive immunity; anti-influenza; cross immunity; cytokine; flu transmission; high risk; human disease; immunoregulation; improved; influenza infection; influenza virus vaccine; influenzavirus; mouse model; novel; porcine model; respiratory; swine influenza; therapeutic target; translational model; uptake; vaccine response; vaccine safety; viral transmission

PROJECT SUMMARY: Pulmonary T cells are critical for host protection from influenza A virus (IAV) infections. While current understanding of influenza immunity is focused on conventional MHC-restricted T cells that recognize peptide antigens, unconventional innate-like T cell subsets, such as CD1d-restricted invariant natural killer T (NKT) cells, are emerging as integral components of the respiratory immune system where they play both a protective and immunopathological role in lung disease. This is principally through their production of large amounts of cytokines in barrier organs like the lung where NKT cells preferentially accumulate. Although NKT cell activities are thought to make up a substantial portion of influenza immunity, relatively little is known about their impact on human infections due to a lack of suitable animal models. The current proposal seeks to address this knowledge gap using swine, which offer an excellent translational model to determine the role NKT cells play in shaping human influenza immunity. Using our extensive expertise in porcine NKT cells and the swine influenza challenge model, we propose three aims: Aim 1 will examine the significance of NKT cells as an important host factor contributing to IAV susceptibility. We have already created NKT cell-deficient CD1d knockout (KO) pigs and discovered that they shed less virus than NKT cell-intact pigs. Aim 2 will use the same pig stock to determine how NKT cells shape the pre-existing immunity afforded by inactivated and modified live virus vaccines. Addressing this question is important to inform vaccinologists since NKT cells have previously been found to generate immune responses that could stimulate durable protection against viral infections. Aim 3 will use our CD1d-KO pigs to determine whether NKT cells modulate vaccine associated enhanced respiratory disease (VAERD), which is a dangerous condition caused by the use of inactivated IAV vaccines containing a virus of the same hemagglutinin subtype as the subsequent challenge strain, but with substantial antigenic shift. This induces non-neutralizing IgG Abs that enhances virus uptake into the target cells. These independent but interconnected aims strongly align with the goals of this funding opportunity: to develop novel models that will accurately reflect influenza immunity in humans, including to better mimic pre-existing immunity for vaccine responses and to better understand special high-risk human populations. Our findings should be of considerable value for reducing influenza transmission and improving vaccine safety and efficiency as there are several therapeutic options to modulate the frequency and function of NKT cells.

项目概要： 肺 T 细胞对于保护宿主免受甲型流感病毒 (IAV) 感染至关重要。目前 对流感免疫的理解集中于识别肽抗原的常规 MHC 限制性 T 细胞， 非常规的先天性 T 细胞亚群，例如 CD1d 限制的不变自然杀伤 T (NKT) 细胞，正在作为 呼吸免疫系统的组成部分，它们在以下方面发挥保护和免疫病理作用： 肺部疾病。这主要是通过它们在肺等屏障器官中产生大量细胞因子来实现的。 NKT细胞优先积累。尽管 NKT 细胞活性被认为构成流感的很大一部分 由于缺乏合适的动物模型，人们对它们对人类感染的影响知之甚少。这 目前的提案旨在利用猪来解决这一知识差距，猪提供了一个出色的转化模型来确定 NKT 细胞在塑造人类流感免疫力中发挥的作用。利用我们在猪 NKT 细胞和 针对猪流感攻击模型，我们提出了三个目标： 目标 1 将检验 NKT 细胞作为重要病毒的重要性。 导致 IAV 易感性的宿主因素。我们已经培育出 NKT 细胞缺陷型 CD1d 敲除 (KO) 猪，并且 发现它们比 NKT 细胞完整的猪散发的病毒更少。目标 2 将使用相同的猪群来确定 NKT 如何 细胞形成灭活和改良活病毒疫苗所提供的预先存在的免疫力。解决这个问题的方法是 告知疫苗学家很重要，因为之前已发现 NKT 细胞可以产生免疫反应，从而可以 刺激针对病毒感染的持久保护。目标 3 将使用我们的 CD1d-KO 猪来确定 NKT 细胞是否 调节疫苗相关的增强呼吸道疾病 (VAERD)，这是一种因使用疫苗而引起的危险状况 灭活 IAV 疫苗含有与后续攻击株相同血凝素亚型的病毒，但含有 显着的抗原转变。这会诱导产生非中和性 IgG 抗体，从而增强靶细胞对病毒的摄取。这些 独立但相互关联的目标与本次融资机会的目标高度一致：开发新颖的模型， 将准确反映人类的流感免疫力，包括更好地模拟疫苗反应中预先存在的免疫力 并更好地了解特殊的高危人群。我们的研究结果对于减少 流感传播并提高疫苗的安全性和效率，因为有多种治疗方案可以调节 NKT 细胞的频率和功能。