Assessing the impact of host and virus genetic variability on Filovirus cell entry and infectivity

评估宿主和病毒遗传变异对丝状病毒细胞进入和感染性的影响

• 批准号: MR/S009434/1
• 负责人: Jonathan Ball
• 金额: $ 90.44万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS009434%2F1
• 关键词: Assessing; impact; host; virus; genetic

The first step in virus infection is entry into a susceptible cell. This almost always involves interaction between proteins at the surface of the virus and the cell and, for viruses surrounded by a lipid envelope, subsequent fusion of the virus and host cell membranes. This step of the virus life cycle is the first barrier encountered when a virus jumps from its natural host into another species. We have recently shown that Ebolavirus rapidly evolves to become better adapted for human cell entry but the mechanism underlying this remains to be elucidated. Although the location of key mutations in and around the host protein (receptor) -binding region of the virus surface protein suggest that receptor binding is a key determinant there is increasing evidence to suggest that other steps, for example fusion, may be affected by virus evolution. In this project we will develop a genetically modified mouse, and utilise a range of in vitro assays to study the infectivity of Ebola and Marburg viruses and define how genetic variation observed in both virus and different hosts affects this process. These findings will help us understand better virus spillover events and enable us to identify genetic signatures that may lead to increased zoonotic risk and subsequent human transmissibility as well as identify human populations that are inherently more at risk from heightened outbreaks. Together these findings will lead to improved future outbreak monitoring and response and also inform development of improved vaccines and therapies.

病毒感染的第一步是进入易感细胞。这几乎总是涉及病毒表面的蛋白质与细胞之间的相互作用，对于被脂质包膜包围的病毒，随后病毒与宿主细胞膜的融合。病毒生命周期的这一步是病毒从其自然宿主跳到另一个物种时遇到的第一个障碍。我们最近表明，埃博拉病毒迅速进化，变得更适合人类细胞进入，但其机制仍有待阐明。尽管病毒表面蛋白的宿主蛋白（受体）结合区及其周围的关键突变位置表明受体结合是一个关键决定因素，但越来越多的证据表明其他步骤（例如融合）可能受到病毒进化的影响。在这个项目中，我们将开发一种转基因小鼠，并利用一系列体外试验来研究埃博拉病毒和马尔堡病毒的感染性，并确定在病毒和不同宿主中观察到的遗传变异如何影响这一过程。这些发现将帮助我们更好地了解病毒溢出事件，并使我们能够确定可能导致人畜共患病风险增加和随后的人类传播性的遗传特征，以及确定从加剧疫情中固有风险更高的人群。这些发现将有助于改善未来的疫情监测和应对，并为改进疫苗和疗法的开发提供信息。

项目成果

Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19.

• DOI: 10.1016/j.ymthe.2021.04.022
• 发表时间: 2021-08-04
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Capone S;Raggioli A;Gentile M;Battella S;Lahm A;Sommella A;Contino AM;Urbanowicz RA;Scala R;Barra F;Leuzzi A;Lilli E;Miselli G;Noto A;Ferraiuolo M;Talotta F;Tsoleridis T;Castilletti C;Matusali G;Colavita F;Lapa D;Meschi S;Capobianchi M;Soriani M;Folgori A;Ball JK;Colloca S;Vitelli A
• 通讯作者: Vitelli A

Hepatitis C subtyping assay failure in UK patients born in sub-Saharan Africa: Implications for global treatment and elimination.

• DOI: 10.1002/jmv.28178
• 发表时间: 2023-01
• 期刊: JOURNAL OF MEDICAL VIROLOGY
• 影响因子: 12.7
• 作者: Adeboyejo, Kazeem;King, Barnabas J.;Tsoleridis, Theocharis;Tarr, Alexander W.;McLauchlan, John;Irving, William L.;Ball, Jonathan K.;McClure, C. Patrick
• 通讯作者: McClure, C. Patrick

Arbovirus circulation, epidemiology and spatiotemporal distribution in Uganda.

• DOI: 10.1016/j.ijregi.2023.01.013
• 发表时间: 2023-03
• 期刊: IJID REGIONS
• 作者: Byaruhanga, Timothy;Kayiwa, John T.;Nankya, Annet M.;Ataliba, Irene J.;McClure, C. Patrick;Ball, Jonathan K.;Lutwama, Julius J.
• 通讯作者: Lutwama, Julius J.

Human parainfluenza 2 & 4: Clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes.

• DOI: 10.1111/irv.13012
• 发表时间: 2022-11
• 期刊: INFLUENZA AND OTHER RESPIRATORY VIRUSES
• 影响因子: 4.4
• 作者: Chellapuri, Akhil;Smitheman, Matthew;Chappell, Joseph G.;Clark, Gemma;Howson-Wells, Hannah C.;Berry, Louise;Ball, Jonathan K.;Irving, William L.;Tarr, Alexander W.;McClure, C. Patrick
• 通讯作者: McClure, C. Patrick

In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding.

• DOI: 10.1371/journal.ppat.1010733
• 发表时间: 2022-07
• 期刊: PLoS pathogens
• 影响因子: 6.7