The role of LC3-associated phagocytosis during virus infection

LC 3相关吞噬作用（LC 3-associated phagocytosis，简称LC 3）是近年来发现的一种吞噬途径，在机体对病毒等感染性病原体的免疫过程中发挥重要作用。LC 3与已充分表征的自噬途径具有许多特征，但在LC 3募集至膜的上游信号传导事件中不同。因此，每种途径在体内所起的确切作用一直很难剖析。这项拨款提案的独特之处在于，我们这一代的小鼠缺乏细胞因子，但具有正常的自噬。这使我们能够特别关注在病毒感染的控制中，ESTA发挥的作用。我们使用甲型流感病毒（IAV）感染的病毒缺陷小鼠的初步数据显示，在没有病毒缺陷的情况下，有更高的病毒滴度，更多的炎症和更多的临床体征。因此，我们认为，在呼吸道宿主防御中起着重要作用。该项目的目标是：1。发现了病毒在防御IAV感染机制中的确切作用方式。这将涉及比较病毒感染的进展，在转基因小鼠缺乏与正常小鼠。我们还将研究是否干扰素影响炎症反应，各种类型的免疫反应（抗体和细胞毒性T细胞）以及其他抗病毒反应，如干扰素。发现是否在巨噬细胞或上皮细胞中特异性地发挥作用，在防御IAV。为了做到这一点，我们产生了条件性敲除小鼠，这些小鼠在巨噬细胞中缺乏β-内酰胺酶，但在所有其他组织中却没有。这些小鼠将感染IAV，然后按照目标1进行研究。结果将显著增强我们对病毒感染防御的基本方面以及呼吸生物学方面的理解。 该研究将在利物浦大学和东英吉利大学由一个多学科团队进行，该团队由医学和兽医学院的成员组成，使用目前位于这些地点的设备齐全的设施。自噬缺陷与宿主防御异常、炎症性疾病和年龄相关疾病有关。有可能是细胞凋亡的缺陷，而不是自噬，导致了这些病理状态。与自噬分离的特征将允许以新的光检查与自噬机制相关的病理学。反过来，这可能会导致新的方法来改善抗病毒治疗或治疗干预对病毒感染的后果

LC3-associated phagocytosis (LAP) is a recently-characterised phagocytic pathway that plays important roles during immunity to infectious agents including viruses. LAP shares many features with the well-characterised autophagy pathway but differs in signalling events upstream of LC3 recruitment to membranes. Thus, the precise role played by each pathway 'in vivo' has been very difficult to dissect. The unique aspect of this grant proposal is based on our generation of mice that are deficient in LAP, but have normal autophagy. This allows us to focus specifically on the role played by LAP in the control of viral infection. Our preliminary data using Influenza A virus (IAV) infection of LAP deficient mice reveal that there are higher virus titres, more inflammation and more clinical signs in the absence of LAP. We therefore believe that LAP plays an important role in host defence in the respiratory tract. The aims of this project are to:1. Discover the precise way that LAP acts in the defence mechanisms to IAV infection. This will involve comparing the progress of viral infection in genetically modified mice deficient in LAP with normal mice. We will also study whether LAP influences inflammatory responses, various types of immune responses (antibody and cytotoxic T cell) as well as other anti-viral responses such as interferon.2. Discover whether LAP specifically in macrophages or epithelial cells plays a role in the defence against IAV. To do this, we generate conditional knockout mice that are lacking LAP in macrophages but not in all other tissues. These mice will be infected with IAV and then investigated as in Aim 1.The results will significantly enhance our understanding of fundamental aspects of defence to virus infection as well as aspects of respiratory biology. The research will be carried out at the Universities of Liverpool and UEA by a multi-disciplinary team comprising members of the Medical and Veterinary Faculties using well-equipped facilities currently situated at these sites. Defects in autophagy are associated with aberrant host defence, inflammatory disease and age-related disorders. It is possible that a defect in LAP, rather than autophagy, accounts for some of these pathological conditions. Characterisation LAP separate from autophagy, will allow examination of pathologies linked to autophagic machinery in a new light. In turn this may lead to novel approaches to improving antiviral therapies or therapeutic interventions against the consequences of viral infection