Mechanisms of innate resistance to virus infections

摘要 心功能不全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 问题是，它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)病毒如何在缺乏病毒的情况下从肺传播到心脏 病毒血症，以及4)免疫系统如何影响心脏发病。机械化的主要障碍 在这一领域的研究一直缺乏易于处理的动物模型来概括重要的心脏 严重流感的功能障碍。我们已经通过开发干扰素诱导的方法克服了这个障碍 跨膜蛋白3(IFITM3)KO小鼠作为包括病毒在内的严重流感病毒感染的模型 心脏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是一种先天免疫系统的抗病毒蛋白，在该系统中人类常见的缺陷 种群使个体更容易受到严重感染，使IFITM3 KO小鼠成为相关和 信息性模型。我们将在以下三个目标中利用这一开创性的模式。在目标1中，我们 将决定病毒是否直接在心脏组织中传播和复制是这种病理所必需的 或者流感病毒是否通过严重的全身炎症间接导致心脏功能不全？ 肺部感染。为了解决这一领域的根本争议，我们开发了一种新颖和创新的 重组流感病毒株，具有在心肌细胞中复制的特异性，而在心脏细胞中完全复制 肺部。在目标2中，我们将通过使用以下方法来识别赋予特定病毒株心脏趋向性的病毒特征 与重组病毒的候选病毒基因方法，以及适应性传代方法。在AIM 3、我们将解开流感病毒如何在缺席的情况下具体从肺移动到心脏的谜团 病毒血症和其他器官感染。为此，我们将测试移行免疫细胞感染 促进了病毒向心脏的传播。我们将进一步研究IFITM3在造血系统中的表达 免疫细胞在感染过程中影响病毒的心脏传播和心脏功能障碍。总的来说，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战略 与流感相关的心脏功能障碍。

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.