Modeling the dynamics and evolution of immune responses to influenza viruses

模拟流感病毒免疫反应的动态和进化

• 批准号: 9039535
• 负责人: RUSTOM NOSHIR ANTIA
• 金额: $ 48.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9039535
• 关键词: Address; Affect; Antibodies; Antigen Receptors; Antigens; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Communities; Data; Development; Documentation; Dose; Educational workshop; Epitopes; Evolution; Exhibits; Foundations; Galaxy; Goals; Health; Hemagglutinin; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunological Models; Infection; Influenza; Lead; Lung; Masks; Modeling; Nature; Pathology; Plasma Cells; Play; Programming Languages; Recruitment Activity; Research; Research Infrastructure; Role; Sequence Analysis; Statistical Methods; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transcend; Vaccination; Vaccines; Variant; Virus; Writing; base; design; experimental analysis; flexibility; improved; influenzavirus; mathematical model; model building; next generation sequencing; pathogen; research study; response; tool; tool development; user-friendly

The overall goal of this proposal is to develop quantitative models that describe how prior immunity affects the dynamics and evolution of recall immune responses to influenza viruses. Our goal is to understand the fundamental rules underlying the dynamics of virus and immunity in pathogens that exhibit strain variation, and address the following questions: Why do responses to conserved epitopes not get boosted with each new influenza strain and generate strain-transcending immunity? What is the role of CD8 T cells during recall response, what is the nature of the protection from infection and pathology different cell subsets provide, and why do influenza-specific T cell epitopes show little variation? We will answer these questions through three Specific Aims. In Aim 1, we will build and test compartmental mechanistic models to understand how prior humoral immunity affects recall response to different hemagglutinin molecules of influenza strains. We will develop multi-epitope models that track the dynamics of clones of B cells, plasma cells, antibodies and CD4 T cell help to different virus epitopes on the HA molecule. Our models describe how epitope masking by secreted antibodies raised against previous strains plays a key role in understanding competition between responses to different epitopes. In Aim 2, we will build and test models to understand how prior CD8 T cell immunity affects recall response to influenza. We will develop multi-epitope models for CD8 T cell responses and use them to identify the key parameters that regulate proliferation, competition and differentiation of CD8 T cells. For Aim 3, we will combine the models from Aims 1 and 2 to predict how the combined effect of preexisting humoral and T cell immunity affects the diversity and evolution of preexisting and stimulation of new clones of immune cells following sequential challenge with different influenza strains and vaccines. We will also develop models based on phylodynamic approaches to analyze next-generation sequences of the antigen receptors on virus-specific T and B cells. All our models will be validated through experiments that will be done concurrently in Project 2 of this application. Finally, Aim 4 of this project is devoted to the development and dissemination of user-friendly and powerful modeling tools that can be used by the wider research community for immunological modeling. We will design and write a new R package that allows graphical model building and analysis. We will also develop several tools for sequence analysis based on the BEAST and Galaxy platforms. By tapping into the infrastructure of existing, widely used modeling tools, we will be able to produce tools that are at the same time very user friendly and highly flexible.

该提案的总体目标是开发定量模型，以描述先前的免疫力如何影响 召回免疫反应对流感病毒的动力学和演变。我们的目标是了解 病原体中病毒和免疫力的动力学基础的基本规则，表现出应变变异， 解决以下问题：为什么对保守的表位的回答不会被每个新的回答促进 流感菌株并产生应变转移免疫力？ CD8 T细胞在回忆中的作用是什么 反应，保护和病理的保护性质是什么，不同的细胞子群提供了，以及 为什么流感特异性的T细胞表位显示几乎没有变化？ 我们将通过三个特定目标回答这些问题。在AIM 1中，我们将建造和测试室 理解先前的体液免疫如何影响回忆反应的机理模型 流感菌株的血凝素分子。我们将开发多探针模型来跟踪的动力学 B细胞，浆细胞，抗体和CD4 T细胞的克隆有助于HA分子上不同病毒表位。 我们的模型描述了通过针对先前菌株提出的分泌抗体的表位掩蔽剂如何发挥关键 在理解对不同表位的反应之间的竞争中的作用。在AIM 2中，我们将建立和测试 了解先前的CD8 T细胞免疫如何影响对流感的回忆反应。我们将发展 CD8 T细胞响应的多质质模型，并使用它们来识别调节的关键参数 CD8 T细胞的增殖，竞争和分化。 对于AIM 3，我们将结合AIM 1和2的模型，以预测 先前存在的体液和T细胞免疫会影响先前存在和刺激的多样性和演变 免疫细胞的新克隆在顺序挑战之后与不同的流感菌株和疫苗。我们将 还基于系统动力学方法开发模型，以分析抗原的下一代序列 病毒特异性T和B细胞的受体。我们所有的模型将通过将完成的实验验证 同时在本申请的项目2中。最后，该项目的目标4专门用于开发， 传播更广泛的研究社区可以使用的用户友好和强大的建模工具 用于免疫模型。我们将设计和编写一个新的R软件包，该软件包允许图形模型构建 和分析。我们还将开发几种基于野兽和星系的序列分析工具 平台。通过利用现有的，广泛使用的建模工具的基础架构，我们将能够生产 同时非常用户友好且高度灵活的工具。