Immunological responses to emerging phlebo- and arenaviruses

对新出现的静脉病毒和沙粒病毒的免疫反应

• 批准号: MR/N002091/1
• 负责人: Thomas Bowden
• 金额: $ 56.32万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN002091%2F1
• 关键词: Immunological; responses; emerging; phlebo; arenaviruses

Emerging New World arena- and phlebo-viruses are threats to human health for which there are no preventative vaccines or therapeutic treatments. Upon infection of a previously unexposed human host, such pathogens often cause rapid disease progression and result in high mortality rates. The viral glycoproteins displayed on the surface of these viruses are the primary determinants of the host immune response and thus lead targets in antiviral and vaccine design. The objective of this work is to study the antibody response against these viral glycoproteins, at a molecular level, with the aim of isolating and characterizing monoclonal antibodies that can target and prevent the virus infection cycle. A particular emphasis of this work is to isolate monoclonal antibodies, which can bind and (cross)-neutralise several biomedically important viruses from the same families. Following isolation of monoclonal antibodies, we will apply X-ray crystallography and other biophysical tools to define neutralising epitopes targeted on the virus surface. By analogy to the success in development of monoclonal antibody cocktails to treat Ebola virus infection, the data and reagents produced in this work will provide a platform by which to therapeutically target these dangerous groups of pathogens.

新兴的新世界竞技场和静脉曲张病毒对人类健康构成威胁，目前还没有预防性疫苗或治疗方法。一旦感染以前未接触过的人类宿主，这种病原体通常会导致疾病快速发展，并导致高死亡率。这些病毒表面显示的病毒糖蛋白是宿主免疫反应的主要决定因素，因此在抗病毒和疫苗设计中起主导作用。这项工作的目的是在分子水平上研究针对这些病毒糖蛋白的抗体反应，目的是分离和鉴定能够靶向和预防病毒感染周期的单抗。这项工作的一个特别重点是分离单抗，它可以结合和(交叉)中和来自同一家族的几种具有生物医学意义的重要病毒。在分离出单抗后，我们将应用X射线结晶学和其他生物物理工具来确定针对病毒表面的中和表位。通过类比开发治疗埃博拉病毒感染的单抗鸡尾酒的成功，这项工作中产生的数据和试剂将提供一个平台，通过它来治疗这些危险的病原体群体。

项目成果

Shielding and activation of a viral membrane fusion protein.

病毒膜融合蛋白的屏蔽和激活。

• DOI: 10.1038/s41467-017-02789-2
• 发表时间: 2018-01-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Halldorsson S;Li S;Li M;Harlos K;Bowden TA;Huiskonen JT
• 通讯作者: Huiskonen JT

Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1.

• DOI: 10.1128/jvi.01048-18
• 发表时间: 2019-01-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Pryce R;Ng WM;Zeltina A;Watanabe Y;El Omari K;Wagner A;Bowden TA
• 通讯作者: Bowden TA

Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.

• DOI: 10.1128/mbio.02531-20
• 发表时间: 2021-08-31
• 期刊: mBio
• 影响因子: 6.4
• 作者: Rissanen I;Krumm SA;Stass R;Whitaker A;Voss JE;Bruce EA;Rothenberger S;Kunz S;Burton DR;Huiskonen JT;Botten JW;Bowden TA;Doores KJ
• 通讯作者: Doores KJ

Native functionality and therapeutic targeting of arenaviral glycoproteins.

• DOI: 10.1016/j.coviro.2016.04.001
• 发表时间: 2016-06
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Crispin M;Zeltina A;Zitzmann N;Bowden TA
• 通讯作者: Bowden TA

Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody

• DOI: 10.1101/2020.04.17.029876
• 发表时间: 2020-04
• 期刊: bioRxiv
• 作者: I. Rissanen;R. Stass;S. A. Krumm;J. Seow;R. Hulswit;G. Paesen;J. Hepojoki;O. Vapalahti;Å. Lundkvist;O. Reynard;V. Volchkov;K. Doores;J. Huiskonen;T. Bowden