[Monkey Pox] Rapid Research Response

[猴痘] 快速研究反应

• 批准号: BB/X011542/1
• 负责人: Bryan Charleston
• 金额: $ 84.41万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX011542%2F1
• 关键词: Monkey; Pox; Rapid; Research; Response

The project proposes a rapid response to the current monkeypox virus (MPXV) epidemic. It is led by the Pirbright Institute and the Centre for Virus Research - Glasgow - the two UKRI-funded institutes that lead on virus infections of animals and humans - and brings together relevant expertise from several other UK universities and institutions including the Universities of Cambridge, Oxford, Birmingham, Edinburgh and Surrey, Dstl, UKHSA, Guys and St Thomas NHS.Between April and 18th July 2022, there have been 2137 confirmed cases of human monkeypox (MPX) in UK and the WHO has reported infections in all 5 WHO regions and 50 member states. The current epidemic is the largest ever known for MPXV. An urgent response to this growing epidemic is needed.The consortium assembled proposes 6 inter-related work packages as follows. 1. Genomic characterisation of MPXV.2. Examination of possible virus spillover from humans to UK animals3. Study of the intrinsic and innate barriers to MPXV infection, and MPXV immune evasion strategies4. Study of the immune response to MPXV infection and vaccination5. Development of anti-viral drugs and monitoring for emergence of MPXV drug resistance6. To develop point of care diagnostic tests for MPXVWP 1. This will undertake sequencing of MPXV genomes isolated from humans in UK and monitor virus evolution and adaptation to humans. The sequencing will pay particular attention to the acquisition of genome mutations that might affect virus replication, transmission, virulence or drug resistance and links to WP5.WP2. MPXV has a natural reservoir in rodents in parts of Africa and has a relatively broad host range that includes North American rodents, primates and humans. The widespread human infections provide a possible opportunity for human to animal transmission. This WP will evaluate this potential by examining the ability of MPXV to infect primary cells from a variety of UK animals.WP3. This WP will evaluate the host response to infection by measuring the transcriptomic and proteomic responses to infection of human cells and testing the roles of specific host proteins in protecting against MPXV infection. Further, the ability of MPXV to counteract these defences will be tested building on what has been learnt from studies of related orthopoxviruses.WP4. The immune response to MPXV infection of humans will be measured by determining the antibody and T cell responses. These will be compared with the responses to vaccination using the smallpox vaccine. A specific aim will be to identity signature T cell responses that are characteristic of MPXV infection. In addition to information vaccination programmes, the development of specific tests for immune monitoring will be undertaken.WP5. This WP is concerned with the development of anti-MPXV drugs and builds on the development of CRUSH (COVID-19 Drug Screening and Resistance Hub) at CVR-Glasgow. Currently, 2 drugs are licensed for use against MPXV and these each target a specific virus protein, but mutation of these proteins can lead to drug resistance. The WP proposes to screen additional FDA-approved drugs that have activity against VACV for activity against MPXV. Cyclosporin A and non-immunosuppressive derivatives will be included since these target a proviral cellular protein, cyclophilin A, and therefore emergence of virus resistance is difficult.WP 6. This will develop point of care (POC) diagnostic tests for MPXV. Currently, MPXV infection is confirmed by polymerase chain reaction (PCR), which is specific and sensitive but requires a specialist laboratory. A POC test (such as developed for SARS-CoV-2) would be of great benefit to speed diagnosis. Two approaches will be tried: a Lateral flow test (LAT) and a loop-mediated isothermal amplification (LAMP)-based assay.

该项目提出对当前猴痘病毒（MPXV）流行做出快速反应。该研究由皮尔布赖特研究所和格拉斯哥病毒研究中心领导，这两家由 UKRI 资助的研究机构负责动物和人类的病毒感染研究，并汇集了其他几所英国大学和机构的相关专业知识，包括剑桥大学、牛津、伯明翰、爱丁堡和萨里、Dstl、UKHSA、Guys 和 St Thomas NHS。2022 年 4 月至 7 月 18 日期间，已发生 2137 起英国确诊了人类猴痘（MPX）病例，世界卫生组织已报告了世界卫生组织所有 5 个地区和 50 个成员国的感染情况。目前的流行病是 MPXV 已知的最大规模的流行病。需要对这一日益严重的流行病做出紧急反应。该联盟提出了以下 6 个相互关联的工作包。 1. MPXV 的基因组特征。2．检查病毒可能从人类传播到英国动物3。 MPXV感染的内在和先天障碍以及MPXV免疫逃避策略的研究4。 MPXV 感染和疫苗接种的免疫反应研究5。抗病毒药物的开发和监测 MPXV 耐药性的出现6。开发 MPXVWP 的护理点诊断测试 1。这将对英国人类分离的 MPXV 基因组进行测序，并监测病毒进化和对人类的适应。测序将特别关注可能影响病毒复制、传播、毒力或耐药性的基因组突变的获取以及与 WP5.WP2 的联系。 MPXV 在非洲部分地区的啮齿动物体内有天然宿主，宿主范围相对广泛，包括北美啮齿动物、灵长类动物和人类。广泛的人类感染为人与动物之间的传播提供了可能的机会。该 WP 将通过检查 MPXV 感染来自多种英国动物的原代细胞的能力来评估这种潜力。WP3。该工作组将通过测量人类细胞感染的转录组和蛋白质组反应并测试特定宿主蛋白在防止 MPXV 感染中的作用来评估宿主对感染的反应。此外，MPXV 对抗这些防御的能力将根据从相关正痘病毒研究中学到的知识进行测试。WP4。通过测定抗体和 T 细胞反应来测量人类对 MPXV 感染的免疫反应。这些将与使用天花疫苗接种的反应进行比较。具体目标是识别 MPXV 感染特征的 T 细胞反应特征。除了信息疫苗接种计划外，还将开发免疫监测的具体测试。WP5。该 WP 关注抗 MPXV 药物的开发，并以 CVR-Glasgow 的 CRUSH（COVID-19 药物筛选和耐药性中心）的开发为基础。目前，有两种药物被许可用于对抗 MPXV，每种药物都针对特定的病毒蛋白，但这些蛋白的突变可能导致耐药性。 WP 建议筛选其他 FDA 批准的具有抗 VACV 活性的药物，以了解抗 MPXV 的活性。将包括环孢菌素 A 和非免疫抑制衍生物，因为它们靶向前病毒细胞蛋白亲环蛋白 A，因此很难出现病毒耐药性。WP 6. 这将为 MPXV 开发护理点 (POC) 诊断测试。目前，MPXV感染是通过聚合酶链反应（PCR）来确诊的，该反应具有特异性和敏感性，但需要专业实验室。 POC 测试（例如针对 SARS-CoV-2 开发的测试）对于加快诊断速度将大有裨益。将尝试两种方法：侧向流动测试（LAT）和基于环介导等温扩增（LAMP）的测定。

项目成果

Quantitative proteomics defines mechanisms of antiviral defence and cell death during modified vaccinia Ankara infection

定量蛋白质组学定义了改良痘苗安卡拉感染期间的抗病毒防御和细胞死亡机制

• DOI: http://dx.10.1038/s41467-023-43299-8
• 发表时间: 2023
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Albarnaz J

T cells are ready for the fight against monkeypox.

T 细胞已准备好对抗猴痘。

• DOI: http://dx.10.1016/j.chom.2022.11.004
• 发表时间: 2022
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Wellington D

Temperature elevation synergises with and enhances the type-I IFN-mediated restriction of MPXV

温度升高协同并增强 I 型 IFN 介导的 MPXV 限制

• DOI: http://dx.10.1101/2023.09.29.560106
• 发表时间: 2023
• 作者: Davis C

TRIM5a restricts poxviruses and is antagonized by CypA and the viral protein C6.

TRIM5a 限制痘病毒并被 CypA 和病毒蛋白 C6 拮抗。

• DOI: http://dx.10.1038/s41586-023-06401-0
• 发表时间: 2023
• 期刊: Nature
• 影响因子: 64.8
• 作者: Zhao Y

Perspective on the application of genome sequencing for monkeypox virus surveillance.

基因组测序在猴痘病毒监测中的应用前景。

• DOI: http://dx.10.1016/j.virs.2023.03.006
• 发表时间: 2023
• 期刊: Virologica Sinica
• 影响因子: 5.5
• 作者: Chen Y