[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.

该项目提议对目前的猴痘病毒流行病作出快速反应。它由Pirbright研究所和病毒研究中心领导-格拉斯哥-这两个由英国研究所资助的研究动物和人类病毒感染的研究所-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，牛津大学，伯明翰大学，爱丁堡大学和萨里大学，DSTL，UKHSA，Guys和St托马斯NHS。在英国已经有2137例人猴痘（MPX）确诊病例，并且WHO已经在所有5个WHO区域和50个成员国报告了感染。目前的流行是有史以来最大的MPXV。需要对这一日益严重的流行病作出紧急反应。联合会提出了以下6个相互关联的工作包。1. MPXV.2的基因组表征。检查病毒可能从人类传播到英国动物3。研究MPXV感染的内在和先天屏障，以及MPXV免疫逃避策略4。MPXV感染和疫苗接种的免疫应答研究5.抗病毒药物的开发和监测MPXV耐药性的出现6.开发MPXVWP 1的床旁诊断测试。这将对从英国人类分离的MPXV基因组进行测序，并监测病毒的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得，以及与WP 5.WP 2的联系。MPXV在非洲部分地区的啮齿动物中具有天然水库，并且具有相对广泛的宿主范围，包括北美啮齿动物，灵长类动物和人类。人类感染的广泛传播为人畜传播提供了可能的机会。本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。该WP将通过测量人类细胞感染的转录组学和蛋白质组学反应，并测试特定宿主蛋白在保护免受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在从相关正痘病毒研究中学到的基础上进行测试。将通过测定抗体和T细胞应答来测量人对MPXV感染的免疫应答。这些结果将与使用天花疫苗接种的反应进行比较。一个具体的目标将是识别MPXV感染的特征性T细胞应答。除了宣传疫苗接种方案外，还将加快发展免疫监测的具体测试。该WP关注抗MPXV药物的开发，并建立在CVR格拉斯哥的CRUSH（COVID-19药物筛选和耐药性中心）的开发基础上。目前，有两种药物被许可用于对抗MPXV，每种药物都靶向特定的病毒蛋白，但这些蛋白的突变可能导致耐药性。WP建议筛选其他FDA批准的对VACV有活性的药物，以对抗MPXV。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素A，因此难以出现病毒抗性。这将为MPXV开发床旁（POC）诊断测试。目前，MPXV感染是通过聚合酶链反应（PCR）确认的，该反应具有特异性和敏感性，但需要专业实验室。POC测试（例如为SARS-CoV-2开发的测试）将对快速诊断非常有益。将尝试两种方法：侧流试验（LAT）和基于环介导等温扩增（LAMP）的试验。

项目成果

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

• DOI: 10.1016/j.virs.2023.03.006
• 发表时间: 2023-04
• 期刊: VIROLOGICA SINICA
• 影响因子: 5.5
• 作者: Chen, Yuda;Wu, Changcheng;Ruhan, A.;Zhao, Li;Zhang, Zhongxian;Tan, Wenjie
• 通讯作者: Tan, Wenjie

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

• DOI: 10.1038/s41467-023-43299-8
• 发表时间: 2023-12-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Albarnaz, Jonas D.;Kite, Joanne;Oliveira, Marisa;Li, Hanqi;Di, Ying;Christensen, Maria H.;Paulo, Joao A.;Antrobus, Robin;Gygi, Steven P.;Schmidt, Florian I.;Huttlin, Edward L.;Smith, Geoffrey L.;Weekes, Michael P.
• 通讯作者: Weekes, Michael P.

T cells are ready for the fight against monkeypox.

• DOI: 10.1016/j.chom.2022.11.004
• 发表时间: 2022-12-14
• 期刊: CELL HOST & MICROBE
• 影响因子: 30.3
• 作者: Wellington, Dannielle;Dong, Tao
• 通讯作者: Dong, Tao