Mechanisms of innate resistance to virus infections

对病毒感染的先天抵抗机制

• 批准号: 10367235
• 负责人: Jacob Yount
• 金额: $ 47.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10367235
• 关键词: Address; Animal Model; Area; Attenuated; Autopsy; Bone Marrow; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Chimera organism; Clinical; Custom; Data; Dose; Engineering; Event; Fibrosis; Foundations; Functional disorder; Funding; Genes; Genetic; Genetic Determinism; Heart; Hematopoietic; Human; Immune; Immune system; Immunity; Individual; Infection; Inflammation; Inflammatory; Influenza; Innate Immune System; Integral Membrane Protein; Interferons; Knockout Mice; Knowledge; Laboratory mice; Lung; Maps; Measurement; Modeling; Monitor; Mouse Strains; Mus; Mutation; Myocardial dysfunction; Myocarditis; Natural Immunity; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Population; Positioning Attribute; Process; Proteins; Pulmonary Inflammation; Reassortant Viruses; Recombinants; Reporting; Research; Resistance; Role; Seasons; Testing; Tissues; Tropism; Vaccination; Viral; Viral Genes; Viremia; Virus; Virus Diseases; Virus Replication; Work; flu; genetic risk factor; heart cell; heart damage; heart function; human mortality; influenza infection; influenza virus strain; influenzavirus; information model; innovation; lung injury; mouse model; novel; pandemic disease; pandemic influenza; prevent; reverse genetics; seasonal influenza; systemic inflammatory response; theories; trafficking; virus genetics; virus host interaction

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。尽管流感病毒感染的心脏并发症是清晰识别的临床 问题，它们在致病机制方面对它们的研究很差。我们缺乏对 1）流感病毒是直接还是间接引起心脏损伤，2）哪种病毒特征有助于心脏 某些菌株的对流，3）病毒如何在不存在的情况下专门向心脏传播 病毒血症和4）免疫系统如何影响心脏发病机理。机械的主要障碍 在该领域的研究缺乏可易于概括心脏的动物模型 严重流感的功能障碍。我们通过开发干扰素引起的克服了这一障碍 跨膜蛋白3（IFITM3）KO小鼠是包括病毒的严重流感病毒感染的模型 心脏复制和明显的心脏电气功能障碍，炎症和纤维化。重要的是， IFITM3是先天免疫系统的抗病毒蛋白，其中人类常见缺陷 人口使个人更容易受到严重感染的影响，使IFITM3 KO小鼠成为相关的，并且 信息模型。在以下三个目标中，我们将利用这种开创性模型。在AIM 1中，我们 将确定该病理中是否需要在心脏组织中直接在心脏组织中的病毒传播和复制 或流感病毒是否通过严重的全身性炎症间接诱导心脏功能障碍 感染的肺。为了解决该领域的这一基本争议，我们开发了一种小说和创新的 重组流感病毒菌株具有特异性复制在心脏细胞中，同时完全复制 肺。在AIM 2中，我们将通过使用的病毒特征来鉴定特定的特定病毒菌株通过使用心脏的菌株 候选病毒基因方法，具有重新分类病毒，以及适应性的传代方法。目标 3，我们将解决流感病毒在缺席的情况下如何从肺部转移到心脏的奥秘。 病毒血症和其他器官感染。为此，我们将测试迁移免疫细胞的感染 促进病毒贩运到心脏。我们将进一步研究造血中的IFITM3表达如何 免疫细胞会影响感染过程中病毒和心脏功能障碍的心脏传播。总体而言，我们的 研究将在流感领域回答基本问题，并将揭示作战的新策略 流感相关的心脏功能障碍。