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的研究已经进行了很多研究，但对于流感融合蛋白hemagglutinin的方式而言，宿主酶的处理方式鲜为人知。此外，直到最近才鉴定出一些宿主的流感激活酶。我们已经在人类呼吸道内的细胞中确定了一种这种酶。迄今为止，宿主酶对流感血凝素激活的当前教条是，裂解位点存在的氨基酸序列决定了将进行融合蛋白激活的酶的类型。基于文献和最新发现，我们认为这种血凝素激活的观点过于简单，并且存在其他关键的病毒血凝素和宿主酶相互作用的关键决定因素，从而导致蛋白质的加工和活化。在此提案中，我们旨在阐明影响这种相互作用过程的力以及影响且对发生相互作用至关重要的影响的流感hemagglutinin的结构特征。为此，我们将使用复杂而尖端的生化，生物物理和分子技术来研究H1和H3亚型病毒与两种宿主的流感激活酶的相互作用，一种是几年前已鉴定出来的，而我们最近已鉴定出来的一种。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，从而导致它们的激活。该研究计划应通过提供有关病毒蛋白如何与在宿主中激活其激活的酶相互作用的基本信息，对病毒学领域产生重大影响。它还应该在学术环境和有兴趣发展新型流感抗病人的生物技术/药物领域的研究人员中提供重要信息。加拿大人将通过新的加拿大知识产权以及通过新的抗病毒疗法的发展来从经济上从经济上受益。