Dynamics and Evolution of Immune Responses to Influenza Viruses

 描述（由申请方提供）：本提案的总体目标是定量了解既往免疫如何影响对病毒的回忆免疫应答的动态和演变。这就需要建立免疫和感染后病毒和免疫动力学的数学模型，并通过实验验证模型。我们选择流感系统是因为其易处理性（能够调节病毒的抗原特性并测量小鼠模型感染中的免疫反应），在人类免疫或感染后可获得样品，以及其与人类健康的直接相关性。我们组建了一个多学科团队，在小鼠和人类流感的理论和实验研究方面都具有专业知识。该多PI提案的PI Rustom Antia和Rafi Ahmed是长期合作者，在将建模与免疫学实验数据集成方面拥有丰富的经验。该团队包括：乔希·雅各布（B & T细胞对流感的反应），Brian Evavold & Veronika Zarnitsyna（T细胞反应/亲和力/多样性），Jacob Kohlmeier（常驻记忆T细胞/流感），Anice Lowen和John Steel（流感病毒工程）在埃默里大学加入安德烈亚斯汉德尔（UGA：建模/统计学/T细胞多样性/流感）; Paul托马斯（St. Judes：小鼠/人类流感），以及特雷弗贝德福德和埃里克马特森（FHCRC：流感动力学/统计学）。在项目1目标1中，我们将开发免疫后体液应答动力学模型。在目标2中，我们模拟了CD 8 T细胞对流感病毒的应答，重点是肺中的常驻记忆CD 8 T细胞。目标3结合了目标1和目标2的模型，以生成一个预测模型，用于预测预先存在的流感免疫力如何影响新毒株攻击后的病毒动态和免疫力。我们将使用竞争动力学方法来推断来自测序病毒特异性B和T细胞的B和T细胞克隆竞争的动力学。目标4致力于开发和传播用户友好的建模工具，可供更广泛的研究社区用于免疫学建模。在项目2的目标1-3中，我们将通过跟踪对反向遗传衍生流感病毒的免疫应答（以修饰的B和T细胞表位和重组血凝素（HA）蛋白作为病毒抗原），在小鼠系统中验证项目1相应目标1-3的模型。这将导致项目1中的进一步模型开发。最后，在项目2的目标4中，我们将使用从三价流感疫苗接种研究和自然流感感染研究中获得的人类样本来测试我们验证和改进的n小鼠系统模型的一致性。我们开发的经过验证的模型将为探索改进流感和其他病原体疫苗接种的不同策略奠定基础。

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a quantitative understanding of how prior immunity affects the dynamics and evolution of recall immune responses to viruses. This requires developing mathematical models for the dynamics of virus and immunity following immunization and infection and validating the models experimentally. We choose the influenza system because of tractability (the ability to modulate the antigenic properties of the virus and measure the immune responses in model infections of mice), access to samples following immunization or infection of humans, and its direct relevance to human health. We have assembled a multi-disciplinary team with expertise in both theory and experimental studies in mice and humans influenza. The PI's of this multi-PI proposal Rustom Antia and Rafi Ahmed are long-term collaborators with experience in integrating modeling with experimental data in immunology. The team includes: Joshy Jacob (B & T cell responses to influenza), Brian Evavold & Veronika Zarnitsyna (T cell responses /affinity/diversity), Jacob Kohlmeier (resident memory T cells/influenza), Anice Lowen and John Steel (influenza virus engineering) at Emory University joined by Andreas Handel (UGA: modeling/statistics/T cell diversity/influenza); Paul Thomas (St. Judes: influenza in mice/humans), and Trevor Bedford and Erick Matsen (FHCRC: phylodynamics/statistics). In Project 1 Aim 1 we will develop models for the dynamics of humoral responses following immunization. In Aim 2 we model CD8 T cell responses to influenza viruses with focus on resident memory CD8 T cells in the lungs. Aim 3 combines models from Aim 1, 2 to generate a predictive model for how pre-existing immunity to influenza affects the dynamics of virus and immunity following challenge with new strains. We will use phylodynamics approach to infer the dynamics of B and T cell clones competition from sequencing virus- specific B and T cells. Aim 4 is devoted to the development and dissemination of user-friendly modeling tools that can be used by the wider research community for immunological modeling. In Project 2 Aims 1-3 we will validate our models from the corresponding Aims 1-3 of Project 1 in the mouse system by following the immune responses to reverse genetics-derived influenza viruses with modified B and T cell epitopes and recombinant hemagglutinin (HA) protein as viral antigens. This will lead to further model development in Project 1. Finally, in Aim 4 of Project 2 we will test the consistency of our verified and refined n mouse system models using humans samples banked from studies on vaccination with trivalent influenza vaccines and natural influenza infection. The validated models we develop will lay the foundation to explore different strategies for improving vaccination to influenza and other pathogens.