G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation

G2P-英国；

• 批准号: MR/W005611/1
• 负责人: Wendy Barclay
• 金额: $ 512.48万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW005611%2F1
• 关键词: G2P; UK; National; Virology; Consortium

There have been almost 100 million cases of SARS-CoV-2 infections world-wide, with more than two million deaths to date. It seems certain that this virus will permanently establish itself in the human population and become endemic, meaning that multiple strategies and measures will be needed to prevent, control and treat SARS-CoV-2 infections for the foreseeable future. For all viral infections, the outcomes in terms of disease, recovery, viral persistence or onward transmission are dictated by the balance between virus replication and the immune responses of the infected individuals. As SARS-CoV-2 continues to circulate in people this balance will change over time; On one hand the virus that emerged from an animal source may further adapt to its new human host and on the other hand the acquired immune response in the human population will accumulate potentially limiting viral spread.New variants of SARS CoV-2 with mutations in the genome (different 'genotype') will emerge and some may have altered biological properties ("phenotype"): including transmitting between humans more readily, exacerbating or attenuating disease and mortality, spreading to other animal species (to establish non-human reservoirs) or evading human immunity that is acquired through natural infection or vaccination. The latter is a particular concern at this moment in time given that population-level immunity is increasing as a result of high virus circulation and vaccination programs. Many variants of SARS-CoV-2 are now appearing globally, and the rational assessment of the risks they pose to society requires an evidence-based scientific understanding of any causative changes in biological properties. The Genotype-to-Phenotype UK National Virology Consortium (G2P-UK) will address this critical knowledge gap by leveraging the combined virological expertise of ten leading research centres to undertake a suite of directed and complementary experimental tests that will link SARS-CoV-2 sequence variation to virus behaviour and function. Tests will include the detailed assessments of virus growth using a series of laboratory models of infection, susceptibility of viruses to inhibition by human immune mechanisms including antibodies, evaluations of the functionality of individual virus proteins, and virus propagation and transmissibility using established small animal models. Co-ordination within G2P will be achieved through upfront agreed methodologies and standards, the free exchange of materials, specimens and know-how, regular scientific meetings and a dedicated consortium website. SARS-CoV-2 variants of concern that warrant focused investigation will be prioritised through co-ordinated workings with scientists at another consortium, COG-UK, who are responsible for virus surveillance and keeping track of emerging virus variants. Variants of concern will be selected on criteria that include altered disease outcomes, rapid emergence or spread, infections in the context of pre-existing immunity, apparent or inferred escape from immunity, or resistance to anti-viral drugs.G2P will also engage closely with other key UK organisations and scientific consortia including UK-wide Public Health laboratories and UK-CIC (Coronavirus Immunology Consortium), as well as other leading groups working in the UK and internationally, to gather the most holistic and incisive evaluation of the biological phenotypes of variants of concern and the associated risks they carry. These conclusions will be shared rapidly and openly with key groups such as NERVTAG and SAGE to inform national pandemic management and strategies for patient treatment, diagnostics, population-level surveillance, infection control and vaccination.

迄今为止，全球已有近1亿例SARS-CoV-2感染病例，其中200多万人死亡。似乎可以肯定的是，这种病毒将永久地在人群中扎根并成为地方性疾病，这意味着在可预见的未来，需要采取多种战略和措施来预防、控制和治疗SARS-CoV-2感染。对于所有病毒感染而言，疾病、恢复、病毒持续存在或继续传播的结果取决于病毒复制与受感染个体免疫反应之间的平衡。随着SARS-CoV-2继续在人群中传播，这种平衡将随着时间的推移而改变；一方面，从动物来源产生的病毒可能进一步适应其新的人类宿主，另一方面，人类群体中的获得性免疫反应将积累，可能限制病毒的传播。基因组发生突变的SARS CoV-2的新变种（不同的“基因型”）将出现，其中一些可能改变了生物学特性（“表型”）：包括更容易在人与人之间传播，加剧或减少疾病和死亡率，传播到其他动物物种（建立非人类宿主）或逃避通过自然感染或疫苗接种获得的人类免疫。鉴于由于病毒高传播和疫苗接种计划，人口水平的免疫力正在提高，后者是目前特别令人关注的问题。SARS-CoV-2的许多变体目前正在全球范围内出现，要合理评估它们对社会构成的风险，就需要对生物特性的任何致病变化有基于证据的科学理解。英国基因型-表型国家病毒学联盟（G2P-UK）将利用10个领先研究中心的综合病毒学专业知识，开展一套定向和互补的实验测试，将SARS-CoV-2序列变异与病毒行为和功能联系起来，从而解决这一关键知识缺口。测试将包括使用一系列实验室感染模型对病毒生长进行详细评估、病毒对包括抗体在内的人类免疫机制抑制的易感性、评估单个病毒蛋白的功能以及使用已建立的小动物模型对病毒的繁殖和传播性进行评估。G2P内部的协调将通过预先商定的方法和标准、材料、标本和专有技术的自由交换、定期科学会议和专门的联盟网站来实现。需要重点调查的SARS-CoV-2变体将通过与负责病毒监测和跟踪新出现的病毒变体的另一个联盟COG-UK的科学家协调工作，优先考虑。将根据以下标准选择值得关注的变异：疾病结局改变、迅速出现或传播、在已有免疫的情况下感染、明显或推断逃离免疫，或对抗病毒药物产生耐药性。G2P还将与英国其他主要组织和科学联盟密切合作，包括英国公共卫生实验室和UK- cic（冠状病毒免疫学联盟），以及其他在英国和国际上工作的领导小组，对关注的变异的生物表型及其携带的相关风险进行最全面和最深刻的评估。这些结论将迅速和公开地与NERVTAG和SAGE等关键团体分享，以便为国家大流行管理和患者治疗、诊断、人口水平监测、感染控制和疫苗接种战略提供信息。

项目成果

Lack of antiviral activity of probenecid in vitro and in Syrian golden hamsters.

丙磺舒在体外和叙利亚金仓鼠体内缺乏抗病毒活性。

• DOI: 10.1093/jac/dkad362
• 发表时间: 2024-01-03
• 期刊: The Journal of antimicrobial chemotherapy

SARS-CoV-2 NSP12 associates with the TRiC complex and the P323L substitution is a host adaption

• DOI: 10.1101/2023.03.18.533280
• 发表时间: 2023-03
• 期刊: bioRxiv
• 作者: Muhannad Alruwaili;S. Armstrong;T. Prince;Maximilian Erdmann;D. Matthews;A. Davidson;Waleed Aljabr;J. Hiscox

SARS-CoV-2 variant biology: immune escape, transmission and fitness.

• DOI: 10.1038/s41579-022-00841-7
• 发表时间: 2023-03
• 期刊: Nature reviews. Microbiology

Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.

• DOI: 10.15252/embr.202154322
• 发表时间: 2022-10-06
• 期刊: EMBO reports
• 影响因子: 7.7
• 作者: Cantoni D;Murray MJ;Kalemera MD;Dicken SJ;Stejskal L;Brown G;Lytras S;Coey JD;McKenna J;Bridgett S;Simpson D;Fairley D;Thorne LG;Reuschl AK;Forrest C;Ganeshalingham M;Muir L;Palor M;Jarvis L;Willett B;Power UF;McCoy LE;Jolly C;Towers GJ;Doores KJ;Robertson DL;Shepherd AJ;Reeves MB;Bamford CGG;Grove J
• 通讯作者: Grove J

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein.

• DOI: 10.1038/s41467-023-36745-0
• 发表时间: 2023-03-14
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Calvaresi, Valeria;Wrobel, Antoni G.;Toporowska, Joanna;Hammerschmid, Dietmar;Doores, Katie J.;Bradshaw, Richard T.;Parsons, Ricardo B.;Benton, Donald J.;Roustan, Chloe;Reading, Eamonn;Malim, Michael H.;Gamblin, Steve J.;Politis, Argyris
• 通讯作者: Politis, Argyris