Mechanisms of innate resistance to virus infections

对病毒感染的先天抵抗机制

基本信息

批准号：
10531244
负责人：
Jacob Yount
金额：
$ 46.01万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531244
关键词：
1918 influenza pandemic Address Animal Model Area Attenuated Autopsy Bone Marrow Cardiac Cardiac Myocytes Cell membrane Cells Chimera organism Chromosome Mapping Classification Clinical Custom Data Dose Endowment Engineering Event Fibrosis Functional disorder Funding Genetic Genetic Determinism Heart Hematopoietic Hospitalization Human Immune Immune system Immunity Individual Infection Inflammation Inflammatory Influenza Innate Immune System Integral Membrane Protein Interferons Knockout Mice Knowledge Laboratory mice Lung Lung infections Measurement Modeling Monitor Mouse Strains Mus Mutation Myocardial dysfunction Myocarditis Natural Immunity Organ Pathogenesis Pathogenicity Pathology Patients Population Positioning Attribute Predisposition Process Proteins Reassortant Viruses Recombinants Reporting Research Resistance Role Testing Tissues Tropism Vaccination Viral Viral Genes Viral Proteins Viremia Virus Virus Diseases Virus Replication Work genetic risk factor heart cell heart damage human mortality influenza infection influenza virus strain influenzavirus innovation lung injury mouse model new pandemic novel pandemic influenza prevent reconstitution reverse genetics seasonal influenza systemic inflammatory response theories trafficking virus genetics virus host interaction

项目摘要

SUMMARY Cardiac dysfunction is among the most common extrapulmonary complications of severe influenza virus infections. Although the heart complications of influenza virus infection are a clearly recognized clinical problem, they are poorly studied in terms of pathogenic mechanisms. We lack basic scientific understanding of 1) whether influenza virus directly or indirectly causes heart damage, 2) what viral features facilitate cardiac tropism of certain strains, 3) how virus disseminates from the lung specifically to the heart in the absence of viremia, and 4) how the immune system influences heart pathogenesis. The major barrier to mechanistic research in this area has been the lack of tractable animal models that recapitulate significant cardiac dysfunction in severe influenza. We have overcome this obstacle by developing interferon-induced transmembrane protein 3 (IFITM3) KO mice as a model of severe influenza virus infection that includes viral replication in the heart and significant cardiac electrical dysfunction, inflammation, and fibrosis. Importantly, IFITM3 is an antiviral protein of the innate immune system in which common deficiencies in the human population render individuals more susceptible to severe infections, making IFITM3 KO mice a relevant and informative model. We will make use of this groundbreaking model in the following three Aims. In Aim 1, we will determine whether virus dissemination and replication directly in heart tissue is required for this pathology or whether influenza virus indirectly induces heart dysfunction through systemic inflammation from the severely infected lung. To address this fundamental controversy in the field, we have developed a novel and innovative recombinant influenza virus strain with specific inability to replicate in heart cells while being fully replicative in the lung. In Aim 2, we will identify viral features that endow specific virus strains with cardiac tropism by using a candidate viral gene approach with reassortant viruses, as well as an adaptive passaging approach. In Aim 3, we will solve the mystery of how influenza virus moves specifically from the lung to the heart in the absence of viremia and other organ infections. For this, we will test whether infection of migratory immune cells facilitates virus trafficking to the heart. We will further investigate how IFITM3 expression in hematopoietic immune cells influences cardiac dissemination of virus and cardiac dysfunction during infection. Overall, our research will answer fundamental questions in the influenza field, and will reveal new strategies for combatting influenza-associated cardiac dysfunction.

概括心脏功能障碍是严重流感病毒最常见的肺外并发症之一感染。尽管流感病毒感染引起的心脏并发症是临床上公认的问题，其致病机制方面的研究很少。我们缺乏基本的科学认识 1) 流感病毒是否直接或间接导致心脏损伤，2) 哪些病毒特征有利于心脏损伤某些菌株的趋向性，3）在没有病毒的情况下，病毒如何从肺部特异性传播到心脏病毒血症，4) 免疫系统如何影响心脏发病机制。机械化的主要障碍该领域的研究一直缺乏能够重现显着心脏功能的易于处理的动物模型。严重流感时功能障碍。我们通过开发干扰素诱导的药物克服了这一障碍跨膜蛋白 3 (IFITM3) KO 小鼠作为严重流感病毒感染模型，包括病毒心脏复制和显着的心电功能障碍、炎症和纤维化。重要的是， IFITM3 是先天免疫系统的一种抗病毒蛋白，人类中常见的缺陷群体使个体更容易受到严重感染，使 IFITM3 KO 小鼠成为相关且信息模型。我们将在以下三个目标中利用这一开创性的模型。在目标 1 中，我们将确定这种病理学是否需要病毒直接在心脏组织中传播和复制或者流感病毒是否通过严重的全身炎症间接诱发心脏功能障碍？感染的肺部。为了解决该领域的这一基本争议，我们开发了一种新颖且创新的方法重组流感病毒株在心脏细胞中具有特定的无法复制能力，但在心脏细胞中却能完全复制肺。在目标 2 中，我们将通过使用具有重配病毒的候选病毒基因方法，以及适应性传代方法。瞄准 3、我们将解开流感病毒如何在缺席的情况下特异性地从肺部移动到心脏的谜团病毒血症和其他器官感染。为此，我们将测试迁移性免疫细胞是否被感染促进病毒贩运至心脏。我们将进一步研究IFITM3在造血系统中的表达情况免疫细胞影响病毒的心脏传播和感染期间的心脏功能障碍。总体而言，我们的研究将回答流感领域的基本问题，并将揭示抗击流感的新策略流感相关的心脏功能障碍。