Understanding the fundamental mechanisms of viral activation in the host

了解宿主病毒激活的基本机制

• 批准号: 418127-2012
• 负责人: Richter, Martin
• 金额: $ 1.89万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629765
• 关键词: Understanding; fundamental; mechanisms; viral; activation

Although much research has been done on the influenza virus over the years, strikingly very little is known about the way the influenza fusion protein hemagglutinin is processed by host enzymes for it to become infectious. Furthermore, only recently have some of the host influenza activating enzymes been identified. We have identified one such enzyme in the cells lining the respiratory tract of humans. To date the current dogma on influenza hemagglutinin activation by host enzymes is that the amino acid sequence present at the cleavage site dictates the type of enzyme that will carry out the activation of the fusion protein. Based on the literature and on our most recent discoveries, we believe that this view of hemagglutinin activation is overly simplistic and that there exist other crucial determinants of viral hemagglutinin and host enzyme interaction, which lead to the protein's processing and activation. In this proposal we aim to elucidate the forces that govern this interaction process and the structural features of influenza hemagglutinin that influence and that are critical for the interaction to take place. To do so, we will use sophisticated and cutting-edge biochemical, biophysical and molecular techniques to study the interaction of H1 and H3 subtype viruses with two influenza-activating enzymes of the host, one that has been identified a few years ago and one that we have newly identified recently. Thus the long-term goal of this research program is to understand the fundamental forces, structural determinants and mechanisms of the interaction of viral fusion proteins with host enzymes, which lead to their activation. This research program should have a significant impact on the field of virology by providing fundamental information on how viral proteins interact with enzymes that activate them in the host. It should also provide vital information to researchers in both academic settings and in the biotech/pharmaceutical sectors who are interested in developing novel influenza antivirals. Canadians will benefit from this research economically through the generation of novel Canadian intellectual property, and in public health through the future development of new antiviral therapies.

尽管多年来对流感病毒进行了大量研究，但令人惊讶的是，人们对流感融合蛋白血凝素如何被宿主酶加工以使其具有传染性的方式知之甚少。此外，直到最近才鉴定出一些宿主流感激活酶。我们在人类呼吸道内壁的细胞中发现了一种这样的酶。迄今为止，关于宿主酶激活流感血凝素的现行教条是，存在于切割位点的氨基酸序列决定了将进行融合蛋白激活的酶的类型。根据文献和我们最近的发现，我们认为这种血凝素激活的观点过于简单化，并且病毒血凝素和宿主酶相互作用还存在其他关键决定因素，从而导致蛋白质的加工和激活。在本提案中，我们的目标是阐明控制这种相互作用过程的力量以及影响相互作用并对相互作用发生至关重要的流感血凝素的结构特征。为此，我们将使用复杂和尖端的生化、生物物理和分子技术来研究 H1 和 H3 亚型病毒与宿主的两种流感激活酶的相互作用，其中一种是几年前发现的，另一种是我们最近新发现了。因此，该研究计划的长期目标是了解病毒融合蛋白与宿主酶相互作用的基本力、结构决定因素和机制，从而导致其激活。该研究计划通过提供有关病毒蛋白如何与在宿主中激活它们的酶相互作用的基本信息，应该对病毒学领域产生重大影响。它还应该为学术界和生物技术/制药领域对开发新型流感抗病毒药物感兴趣的研究人员提供重要信息。加拿大人将通过产生新颖的加拿大知识产权从经济上受益于这项研究，并通过未来开发新的抗病毒疗法在公共卫生上受益。