[Monkey Pox] Rapid Research Response

该项目提出了对当前猴痘病毒（MPXV）流行的快速反应。它由皮尔布赖特研究所和格拉斯哥病毒研究中心领导，这是两个英国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大学、UKHSA大学、盖伊斯大学和圣托马斯NHS大学。2022年4月至7月18日期间，英国确诊了2137例人类猴痘（MPX）病例，世卫组织报告了世卫组织所有5个区域和50个成员国的感染情况。目前的疫情是已知的最大的MPXV疫情。需要对这一日益严重的流行病作出紧急反应。组建的联合体提出以下6个相互关联的工作包。1. MPXV.2的基因组特征。检查病毒可能从人类传播到英国动物的情况3。MPXV感染的内在和先天屏障及MPXV免疫逃避策略的研究MPXV感染的免疫应答及疫苗接种研究抗病毒药物的发展与MPXV耐药的监测开发MPXVWP 1的护理点诊断测试。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以及与WP5.WP2的联系。MPXV在非洲部分地区的啮齿动物中有天然宿主，宿主范围相对广泛，包括北美啮齿动物、灵长类动物和人类。广泛的人间感染为人向动物传播提供了可能的机会。本研究将通过检测MPXV感染多种英国动物原代细胞的能力来评估这种潜力。该项目将通过测量人类细胞感染的转录组学和蛋白质组学反应来评估宿主对感染的反应，并测试特定宿主蛋白在保护宿主免受MPXV感染中的作用。此外，MPXV抵抗这些防御的能力将在从相关的正痘病毒研究中获得的知识的基础上进行测试。人类对MPXV感染的免疫反应将通过测定抗体和T细胞反应来测定。这些结果将与接种天花疫苗后的反应进行比较。一个特定的目标将是识别具有MPXV感染特征的签名T细胞反应。除了提供信息的疫苗接种规划外，还将开发用于免疫监测的特定测试。该工作计划涉及抗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，有两种药物被批准用于治疗MPXV，每种药物针对一种特定的病毒蛋白质，但这些蛋白质的突变可能导致耐药性。WP建议筛选fda批准的其他具有抗VACV活性的抗MPXV活性的药物。环孢素A和非免疫抑制衍生物将包括在内，因为它们靶向前病毒细胞蛋白，即亲环素A，因此很难出现病毒耐药性。WP 6。这将开发针对MPXV的护理点诊断测试。目前，MPXV感染是通过聚合酶链反应（PCR）确诊的，这种方法具有特异性和敏感性，但需要专门的实验室。POC测试（例如针对SARS-CoV-2开发的测试）将极大地有助于加快诊断速度。将尝试两种方法：横向流动测试（LAT）和环介导等温扩增（LAMP）为基础的分析。

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.