The role of LC3-associated phagocytosis during virus infection

LC3相关吞噬作用在病毒感染过程中的作用

• 批准号: BB/R00904X/1
• 负责人: James Stewart
• 金额: $ 54.94万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR00904X%2F1
• 关键词: role; LC3; associated; phagocytosis; during

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

LC3相关吞噬细胞作用(LAP)是一种新近发现的吞噬细胞途径，在对包括病毒在内的感染性病原体的免疫过程中发挥着重要作用。LAP与特征明确的自噬途径有许多共同之处，但不同之处在于LAP信号转导事件发生在LC3募集到膜上的上游。因此，每一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是基于我们这一代缺乏LAP但具有正常自噬能力的小鼠。这使我们能够特别关注LAP在控制病毒感染方面所起的作用。我们用甲型流感病毒(IAV)感染LAP缺陷小鼠的初步数据显示，在没有LAP的情况下，病毒滴度更高，炎症更多，临床症状更多。因此，我们认为LAP在呼吸道的宿主防御中起着重要作用。这个项目的目的是：1.发现LAP在防御IAV感染机制中的确切作用方式。这将涉及比较LAP基因缺陷小鼠和正常小鼠的病毒感染进展。我们还将研究LAP是否影响炎症反应、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。了解巨噬细胞或上皮细胞中的LAP是否在防御IAV中发挥作用。为了做到这一点，我们产生了条件基因敲除小鼠，巨噬细胞中缺乏LAP，但其他所有组织中都没有。这些小鼠将被感染IAV，然后按照目标1进行调查。结果将极大地增强我们对病毒感染防御的基本方面以及呼吸道生物学方面的了解。这项研究将在利物浦大学和对外经济学院由一个由医学和兽医学院成员组成的多学科小组进行，该小组使用目前位于这些地点的设备齐全的设施。自噬缺陷与异常的宿主防御、炎症性疾病和年龄相关疾病有关。可能是LAP的缺陷，而不是自噬，解释了这些病理情况中的一些。与自噬分离的特征LAP将允许以新的方式检查与自噬机械有关的病理。反过来，这可能导致改进抗病毒治疗或针对病毒感染后果的治疗干预的新方法

项目成果

Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis.

• DOI: 10.1126/sciadv.abn3298
• 发表时间: 2022-10-28
• 期刊: Science advances
• 影响因子: 13.6

Evaluation of Nafamostat as Chemoprophylaxis for SARS-CoV-2 Infection in Hamsters.

• DOI: 10.3390/v15081744
• 发表时间: 2023-08-15
• 期刊: Viruses
• 作者: Neary M;Sharp J;Gallardo-Toledo E;Herriott J;Kijak E;Bramwell C;Cox H;Tatham L;Box H;Curley P;Arshad U;Rajoli RKR;Pertinez H;Valentijn A;Dhaliwal K;Mc Caughan F;Hobson J;Rannard S;Kipar A;Stewart JP;Owen A
• 通讯作者: Owen A

Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain.

通过细胞因子受体与ATG16L1 WD40结构域之间的直接相互作用来调节细胞因子信号传导。

• DOI: 10.1038/s41467-020-19670-4
• 发表时间: 2020-11-20
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Serramito-Gómez I;Boada-Romero E;Villamuera R;Fernández-Cabrera Á;Cedillo JL;Martín-Regalado Á;Carding S;Mayer U;Powell PP;Wileman T;García-Higuera I;Pimentel-Muiños FX
• 通讯作者: Pimentel-Muiños FX

Lack of antiviral activity of probenecid in vitro and in Syrian golden hamsters.

丙磺舒在体外和叙利亚金仓鼠体内缺乏抗病毒活性。

• DOI: 10.1093/jac/dkad362
• 发表时间: 2024-01-03
• 期刊: The Journal of antimicrobial chemotherapy

Constitutive TRIM22 Expression in the Respiratory Tract Confers a Pre-Existing Defence Against Influenza A Virus Infection.

• DOI: 10.3389/fcimb.2021.689707
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Charman M;McFarlane S;Wojtus JK;Sloan E;Dewar R;Leeming G;Al-Saadi M;Hunter L;Carroll MW;Stewart JP;Digard P;Hutchinson E;Boutell C
• 通讯作者: Boutell C