[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.

该项目提出对当前的猴蛋白质病毒（MPXV）流行的快速反应。它由皮尔布赖特研究所（Pirbright Institute）和病毒研究中心（Glasgow）领导 - 格拉斯哥（Glasgow） - 乌克里（Ukri）资助的两家机构引起了动物和人类病毒感染的机构 - 并从其他几所英国大学和机构中汇集了相关的专业知识，包括坎伯里奇大学，牛津大学，伯明翰，伯明翰和苏里堡，distl，distl，lys，thms，thoms，and thoms， 2022年，英国已有2137例确认人类蒙基托克斯（MPX）的病例，以及WHO报告了所有5个WHO地区和50个成员国的感染。当前的流行病是有史以来最大的MPXV。需要对这种日益增长的流行病进行紧急反应。该财团组装提出了6个相互关联的工作包，如下所示。 1。MPXV.2的基因组表征。检查可能从人类到英国动物的病毒溢出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。对MPXV感染和疫苗接种的免疫反应的研究5。抗病毒药物的发展和监测MPXV耐药性的出现6。为了开发MPXVWP 1的护理诊断测试。这将进行从英国人类中分离出的MPXV基因组的测序，并监测病毒的进化和适应对人的适应。该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，并与WP5.WP2联系起来。 MPXV在非洲部分地区具有天然储层，并且具有相对广泛的宿主范围，其中包括北美啮齿动物，灵长类动物和人类。广泛的人类感染为人类进行动物传播提供了可能的机会。该WP将通过检查MPXV感染来自各种英国动物的原代细胞的能力来评估这一潜力。该WP将通过测量对人类细胞感染的转录组和蛋白质组学反应以及测试特定宿主蛋白在预防MPXV感染中的作用，评估宿主对感染的宿主反应。此外，将对MPXV抵消这些防御的能力进行测试。通过确定抗体和T细胞反应来测量对人类MPXV感染的免疫反应。这些将与使用天花疫苗对疫苗接种的反应进行比较。一个具体的目的是对MPXV感染特征的身份签名T细胞反应。除了信息疫苗接种计划外，还将进行特定的免疫监测测试。WP5。该WP涉及抗MPXV药物的开发，并建立在CVR-Glasgow的Crush（Covid-19药物筛查和耐药枢纽）的发展上。目前，有2种药物获得了针对MPXV的许可，并且这些药物靶向特定的病毒蛋白，但是这些蛋白质的突变可以导致耐药性。 WP提议筛选额外的FDA批准药物，这些药物具有针对VAVV活性的MPXV活性。环孢菌素A和非免疫抑制衍生物将被包括在内，因为这些靶向了细胞蛋白，环蛋白A，因此很难抗病病毒的出现。WP6。这将开发MPXV的护理点（POC）诊断测试。目前，通过特定且敏感的聚合酶链反应（PCR）证实了MPXV感染，但需要专业的实验室。 POC测试（例如针对SARS-COV-2开发的）对于加速诊断将有很大的好处。将尝试两种方法：横向流程测试（LAT）和基于循环介导的等温扩增（LAMP）的测定法。

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

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

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.

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

• DOI: 10.1101/2023.09.29.560106
• 发表时间: 2023-10-11
• 期刊: bioRxiv
• 作者: Davis，Chris;Epifano，Ilaria;Boutell，Chris
• 通讯作者: Boutell，Chris