MRC Transition Support Award CDA Edward Hutchinson

MRC 转型支持奖 CDA Edward Hutchinson

• 批准号: MR/V035789/1
• 负责人: Edward Hutchinson
• 金额: $ 55.07万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV035789%2F1
• 关键词: MRC; Transition; Support; Award; CDA

This proposal is for Transition Support to continue the work of a Career Development Award (CDA), which was delayed and redirected in response to a number of unexpected issues. Both the CDA and the current proposal focus on influenza viruses. These cause seasonal influenza, which kills 290 000 - 650 000 people globally each year and is one of the leading global causes of death. As well as causing seasonal illnesses in humans each year, influenza viruses are unusually good at jumping from one species to another, as human and animal influenza viruses can exchange genes if they both infect the same host at the same time. The ready ability of influenza viruses to undergo this 'reassortment,' along with their high mutation rates, enables them to cause repeated and sometimes devastating pandemics.The work in the original CDA focused on proteins in the virus particles that transmit influenza infections. We showed that these were much more variable than was previously appreciated. The host cell and the virus can both strongly influence which proteins are included in virus particles and in what amount, and the proteins themselves can be modified in different ways. We also discovered an entirely new class of 'hidden' influenza virus proteins, and examined how the virus particles produced in natural influenza virus infections can vary in shape, from the spherical particles typically studied in the laboratory to enormously extended filaments. As our work developed, we were able to examine more sources of variation among influenza virus particles: in the genes they carry, in the proteins that make them infectious and the in shapes they adopt.This Transition Support proposal aims to consolidate this work. Work will begin by completing three well-advanced projects that were delayed during the CDA. The first of these draws together multiple lines of evidence to provide a picture of influenza virus particles in unprecedented detail, and showing where these microscopic structures can vary. The second shows how over time an infected cell alters the composition of the virus particles it sheds, making them more infectious just as the surrounding cells start to increase their antiviral defences. The third examines a set of chemical modifications to influenza virus proteins that can act like a series of switches, altering and regulating the proteins' functions.With this work, we will have completed a wide-ranging survey of the ways in which influenza virus particles can vary, and developed many novel tools to study this variation. We will then ask how knowing about the enormous scope for variation among influenza virus particles changes our understanding of what happens when we get infected with influenza. The ability of influenza viruses to swap genes inside their hosts shows us that virus particles can interact during an infection, but most of our understanding of how influenza viruses actually work focusses on understanding the initiation of an infection by one single virus particle. Once an infection is underway in a host, we know that large numbers of highly variable virus particles are shed into a small space and can interact, but we have not yet been able to examine how interactions within this 'viral microenvironment' shape the outcome of an infection. Using the tools we have developed, we will examine for the first time how the single influenza virus particle that infects us, rapidly creates within us a swarm of highly variable virus particles that interact to determine the course of our infection. As well as detailing the course of a normal infection, this will allow us to understand how the 'swarms' created by a human and animal virus could come together to seed the next respiratory virus pandemic.

这项建议是为了过渡支助继续职业发展奖的工作，该工作因一些意外问题而被推迟和改变方向。CDA和目前的提案都侧重于流感病毒。这些导致季节性流感，每年在全球造成290 000 - 650 000人死亡，是全球主要死因之一。除了每年在人类中引起季节性疾病外，流感病毒还非常善于从一个物种跳到另一个物种，因为如果人类和动物流感病毒同时感染同一宿主，它们可以交换基因。流感病毒的这种"重组"能力，沿着它们的高突变率，使它们能够引起反复的、有时是毁灭性的大流行。最初的CDA的工作集中在传播流感感染的病毒颗粒中的蛋白质上。我们发现，这些变量比以前认识到的要多得多。宿主细胞和病毒都可以强烈影响病毒颗粒中包含的蛋白质以及数量，并且蛋白质本身可以以不同的方式进行修饰。我们还发现了一类全新的“隐藏”流感病毒蛋白，并研究了自然流感病毒感染中产生的病毒颗粒如何改变形状，从实验室中通常研究的球形颗粒到巨大的延伸细丝。随着我们工作的发展，我们能够检查流感病毒颗粒之间的更多变异来源：它们携带的基因，使它们具有传染性的蛋白质以及它们采用的形状。工作将开始，完成三个在CDA期间被推迟的先进项目。其中第一个汇集了多条证据线，以前所未有的细节提供了流感病毒颗粒的图片，并显示了这些微观结构的变化。第二个显示了受感染的细胞如何随着时间的推移改变其脱落的病毒颗粒的组成，使它们更具感染性，就像周围的细胞开始增加其抗病毒防御一样。第三部分研究了流感病毒蛋白质的一系列化学修饰，这些修饰可以像一系列开关一样改变和调节蛋白质的功能。通过这项工作，我们将完成对流感病毒颗粒变化方式的广泛调查，并开发出许多新的工具来研究这种变化。然后，我们会问，了解流感病毒颗粒之间的巨大变异范围如何改变我们对感染流感后会发生什么的理解。流感病毒在宿主体内交换基因的能力向我们表明，病毒颗粒在感染过程中可以相互作用，但我们对流感病毒如何实际工作的理解大多集中在理解单个病毒颗粒引发感染。一旦感染在宿主中进行，我们知道大量高度可变的病毒颗粒会脱落到一个小空间中并相互作用，但我们还无法研究这种“病毒微环境”内的相互作用如何影响感染的结果。使用我们开发的工具，我们将首次研究感染我们的单个流感病毒颗粒如何在我们体内迅速产生一群高度可变的病毒颗粒，这些病毒颗粒相互作用以确定我们的感染过程。除了详细描述正常感染的过程外，这将使我们能够了解人类和动物病毒如何创造“群体”，共同播种下一次呼吸道病毒大流行。

项目成果

Analysis of Zika virus capsid-Aedes aegypti mosquito interactome reveals pro-viral host factors critical for establishing infection.

• DOI: 10.1038/s41467-021-22966-8
• 发表时间: 2021-05-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gestuveo RJ;Royle J;Donald CL;Lamont DJ;Hutchinson EC;Merits A;Kohl A;Varjak M
• 通讯作者: Varjak M

The SARS-CoV-2 Spike Protein Mutation Explorer: Using an Interactive Application to Improve the Public Understanding of SARS-CoV-2 Variants of Concern

SARS-CoV-2 刺突蛋白突变探索者：使用交互式应用程序提高公众对所关注的 SARS-CoV-2 变体的了解

• DOI: 10.1101/2022.09.09.507349
• 发表时间: 2022
• 作者: Iannucci S

Using Molecular Visualisation Techniques to Explain the Molecular Biology of SARS-CoV-2 Spike Protein Mutations to a General Audience.

• DOI: 10.1007/978-3-031-10889-1_6
• 发表时间: 2022-01-01
• 期刊: Advances in experimental medicine and biology
• 作者: Iannucci, Sarah;Harvey, William;Poyade, Matthieu
• 通讯作者: Poyade, Matthieu

The mutational variety of the live-attenuated influenza vaccine proteome

减毒流感疫苗蛋白质组的突变多样性

• DOI: 10.1099/acmi.ac2021.po0409
• 发表时间: 2022
• 期刊: Access Microbiology
• 作者: McConnell M

FISHtoFigure: An easy-to-use tool for rapid, multi-target partitioning and analysis of sub-cellular mRNA transcripts in smFISH data

FISHtoFigure：一种易于使用的工具，用于快速、多目标分区和分析 smFISH 数据中的亚细胞 mRNA 转录本

• DOI: 10.1101/2023.06.28.546871
• 发表时间: 2023
• 作者: Bentley-Abbot C