Dynamics and Evolution of Immune Responses to Influenza Viruses

流感病毒免疫反应的动态和进化

• 批准号: 9238642
• 负责人: RUSTOM NOSHIR ANTIA
• 金额: $ 158.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238642
• 关键词: Address; Affect; Affinity; Antibodies; Antigen Receptors; Antigens; B-Lymphocyte Epitopes; B-Lymphocytes; Binding; Biological Models; Birth; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Clone Cells; Collaborations; Communities; Data; Development; Engineering; Epitopes; Evolution; Exhibits; Experimental Models; Fostering; Foundations; Galaxy; Generations; Goals; Head; Health; Hemagglutinin; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunological Models; Immunologics; Immunology; Infection; Infection Control; Influenza; Longevity; Lung; Masks; Measurement; Measures; Memory; Modeling; Mothers; Mus; Nature; Paper; Pathology; Plasma Cells; Play; Population; Property; Proteins; Recombinants; Research; Research Infrastructure; Role; Saint Jude Children' s Research Hospital; Sampling; Sequence Analysis; Statistical Methods; Steel; System; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transcend; Universities; Vaccination; Vaccines; Variant; Viral Antigens; Virus; Writing; base; biodefense; computerized tools; design; experience; experimental study; flexibility; improved; in vivo; influenzavirus; mathematical model; model building; model development; multidisciplinary; next generation; pathogen; predictive modeling; public health relevance; response; reverse genetics; statistics; stem; theories; tool; trivalent influenza vaccine; user-friendly; vaccine development

 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.

 描述（由适用提供）：该提案的总体目标是对先前免疫学如何影响召回免疫学反应对病毒的动态和演变的定量理解。这需要开发用于免疫学和感染后病毒和免疫学动力学的数学模型，并通过实验验证模型。我们之所以选择影响力系统，是因为障碍性（能够调节病毒的抗原特性并测量小鼠模型感染中的免疫学反应），在免疫学或人类感染后获得样品的访问以及其与人类健康的直接相关性。我们已经组建了一个多学科团队，在小鼠和人类影响的理论和实验研究方面都有专家。该多PI建议Rustom Antia和Rafi Ahmed的PI是长期合作者，具有将建模与免疫学实验数据相结合的经验。 The team includes: Joshy Jacob (B & T cell responses to influenceza), 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多样性/流感）；保罗·托马斯（Paul Thomas）（圣裁判术：小鼠/人类的影响力）以及特雷弗·贝德福德（Trevor Bedford）和埃里克·马滕（Erick Matten）（FHCRC：系统动力学/统计学）。在项目1 AIM 1中，我们将开发用于免疫抑制后体液反应动态的模型。在AIM 2中，我们对CD8 T细胞反应进行建模，以影响病毒，重点是居民记忆CD8 T细胞中的肺中的病毒。 AIM 3结合了AIM 1、2的模型，以生成一个预测模型，以实现影响为影响的免疫学如何影响新菌株的挑战后病毒和免疫学的动态。我们将使用系统动力学方法来推断B和T细胞克隆竞争的动力学，从测序病毒特异性B和T细胞。 AIM 4致力于开发和传播用户友好的建模工具，这些工具可以被更广泛的研究社区用于免疫建模。在项目2的目标1-3中，我们将通过遵循免疫反应来从相应的目标1-3中验证我们的模型，从而通过改变遗传学衍生的影响，以改良的B和T细胞表位和重组血凝集素（HA）蛋白作为病毒抗原作为病毒。这将导致项目1中的进一步模型开发。最后，在项目2的AIM 4中，我们将使用对具有三价影响和自然影响的疫苗研究的人类样本来测试经过验证和精制的N小鼠系统模型的一致性。我们开发的经过验证的模型将奠定基础，以探索改善影响力和其他病原体疫苗的不同策略。