Mechanisms of Cardioprotection by the Innate Immune System During Influenza Virus Infections

摘要 尽管流感病毒被认为是感染性心肌炎的原因已有一个多世纪的历史，但 这些心脏并发症的潜在机制和易感因素尚不清楚。 心脏功能不全主要见于严重感染，人类严重流感 重复性与干扰素诱导的跨膜蛋白3(IFITM3)的有害多态相关 吉恩。IFITM3是一种天然免疫蛋白，可阻止病毒进入细胞并调节炎症免疫 小路。尽管知道IFITM3影响人类感染的结局，但它在心脏疾病中的作用 流感的并发症以前没有被调查过。我们的实验使用了一种新开发的 IFITM3基因敲除小鼠模型表明IFITM3对于限制流感病毒传播到心脏是必不可少的 并用于预防病毒引起的心脏纤维化和电功能障碍。我们还观察到， 在感染期间，IFITM3基因敲除小鼠心脏中的免疫细胞被耗尽，从而防止心脏 清除病毒。在目标1中，我们将通过测试 假设驻留在心脏或招募到心脏的IFITM3缺陷免疫细胞直接受到病毒感染 并经历细胞凋亡。在目标2中，我们将确定纤维化和心功能不全的机制。 通过检验病毒感染激活特定炎症和纤维化的假设，在感染期间发生 在缺乏IFITM3的情况下心肌细胞和心脏成纤维细胞的基因图谱。总体而言，我们的研究将 揭示严重流感病毒感染的心脏纤维化和功能障碍的机制，因此 确定抗击这种由感染引起的病理的新策略。

SUMMARY Although influenza virus has been known for more than a century to be a cause of infectious myocarditis, the underlying mechanisms and susceptibility factors for these cardiac complications are not well understood. Cardiac dysfunction is primarily seen in severe infections, and severe influenza in humans has been reproducibly linked to deleterious polymorphisms in the Interferon-Induced Transmembrane Protein 3 (IFITM3) gene. IFITM3 is an innate immune protein that blocks virus entry into cells and regulates inflammatory immune pathways. Despite the knowledge that IFITM3 influences the outcome of human infections, its role in cardiac complications of influenza has not been previously investigated. Our experiments using a newly developed IFITM3 knockout mouse model indicate that IFITM3 is essential for limiting influenza virus spread to the heart and for preventing cardiac fibrosis and electrical dysfunction caused by the virus. We have also observed that immune cells are depleted from hearts of IFITM3 knockout mice during infection, thus preventing cardiac clearance of virus. In Aim 1, we will investigate the cause of this immune cell depletion by testing the hypothesis that IFITM3-deficient immune cells residing in, or recruited to, the heart are directly infected by virus and undergo apoptosis. In Aim 2, we will identify the mechanism by which fibrosis and cardiac dysfunction occur during infection by testing the hypothesis that virus infection activates specific inflammatory and fibrotic gene profiles in cardiomyocytes and cardiac fibroblasts in the absence of IFITM3. Overall, our research will reveal mechanisms underlying cardiac fibrosis and dysfunction in severe influenza virus infections and will thus identify new strategies for combatting this infection-induced pathology.