Mechanisms of innate resistance to virus infections

总结 心功能不全是重症流感病毒最常见的肺外并发症之一 感染.虽然流感病毒感染的心脏并发症是一个明确认识的临床 问题，他们在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害，2）病毒的哪些特征有助于心脏 某些菌株的嗜性，3）病毒如何从肺传播到心脏，特别是在缺乏 病毒血症，以及4）免疫系统如何影响心脏发病机制。机械化的主要障碍 这一领域的研究一直缺乏易于处理的动物模型， 严重流感的功能障碍。我们通过开发干扰素诱导的 作为严重流感病毒感染的模型的跨膜蛋白3（IFITM3）KO小鼠，包括病毒性流感病毒感染， 心脏中的复制和显著的心脏电功能障碍、炎症和纤维化。重要的是， IFITM3是先天免疫系统的抗病毒蛋白，其中人类中的常见缺陷是免疫缺陷。 群体使个体更容易受到严重感染，使IFITM3 KO小鼠成为相关的， 信息模型我们将在以下三个目标中使用这一开创性的模式。目标1： 将确定这种病理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导心脏功能障碍， 肺部感染为了解决该领域的这一根本性争议，我们开发了一种新颖且创新的 在心脏细胞中特异性不能复制而在心脏细胞中完全复制的重组流感病毒株 肺在目标2中，我们将通过以下方法鉴定赋予特定病毒株嗜心性的病毒特征： 候选病毒基因与重组病毒的方法，以及适应性传代方法。在Aim中 3、我们将解开流感病毒如何在没有病毒的情况下特异性地从肺转移到心脏的谜团。 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的感染是否 促进病毒运输到心脏。我们将进一步研究IFITM3在造血细胞中的表达， 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 研究将回答流感领域的基本问题，并将揭示对抗流感的新策略。 流感相关的心功能不全

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.