The Language of Zoonosis: Rationalising Receptor-Mediated Spillover of Viral Pathogens at a Molecular Level

人畜共患病的语言：在分子水平上合理化受体介导的病毒病原体的溢出

• 批准号: MR/S007555/1
• 负责人: Thomas Bowden
• 金额: $ 233.39万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS007555%2F1
• 关键词: Language; Zoonosis; Rationalising; Receptor; Mediated

Despite global advances in virus detection and surveillance, we lack the capability to predict which viruses can cross the species barrier and cause disease. This process is dependent on a number of factors: most importantly, the ability of a virus to target specific cell types by binding to receptors displayed on the host-cell surface. Using a multidisciplinary structural and molecular biology approach, I will define the rules of virus-host receptor engagement for emergent paramyxoviruses and elucidate the molecular mechanism by which paramyxoviruses viruses undergo attachment and fusion with host cells. This will be addressed in the context of both intact virus and the individual structural glycoproteins responsible for viral entry. This investigation will include a focus on animal morbilliviruses, a group of pathogens for which there is a paucity of molecular understanding of host cell entry processes. Principal goals of this work will be to elucidate the mechanism of receptor-mediated entry of paramyxoviruses into a host cell and to reveal viral envelope determinants of cross-species transmission, at a molecular level. This will involve the combination of high-resolution structural studies on isolated molecules with lower resolution analyses of intact viral prototypes. This work will both enhance our understanding of paramyxovirus pathobiology and also allow prediction of the zoonotic risks associated with newly reported viruses. The information derived from these combined techniques will ultimately aid in our ability to combat these pathogens.There are four complementary goals:1. Recombinant expression and purification of paramyxoviral attachment glycoproteins and cognate receptors, preparation of virus-like particles, and the acquisition/development of neutralising antibodies (nAbs) against these glycoproteins.2. Crystallographic analysis of paramyxoviral glycoproteins alone and in complex with cellular receptors and nAbs to provide atomic descriptions in pre- and post-fusion assemblies, and to illustrate the morphological changes required for viral entry.3. Cryo-electron microscopy analysis of intact, non-pathogenic viral orthologues to visualise the ultrastructure of these viruses, the assembly of their subunit glycoproteins, and to provide a structural basis for receptor and antibody interactions for entire virions.4. To complement structure-predicted determinants for virus host cell entry with in vitro functional analyses.

尽管全球在病毒检测和监测方面取得了进展，但我们缺乏预测哪些病毒可以跨越物种屏障并导致疾病的能力。这一过程取决于许多因素：最重要的是，病毒通过结合宿主细胞表面的受体来靶向特定细胞类型的能力。使用多学科的结构和分子生物学的方法，我将定义的规则，病毒宿主受体参与紧急副粘病毒和阐明的分子机制，副粘病毒病毒进行附着和融合与宿主细胞。这将在完整的病毒和负责病毒进入的单个结构糖蛋白的背景下得到解决。这项调查将包括对动物麻疹病毒的关注，这是一组病原体，对宿主细胞进入过程缺乏分子理解。这项工作的主要目标将是阐明受体介导的副粘病毒进入宿主细胞的机制，并揭示跨物种传播的病毒包膜决定因素，在分子水平上。这将涉及对分离分子的高分辨率结构研究与对完整病毒原型的低分辨率分析相结合。这项工作将提高我们对副粘病毒病理生物学的理解，并预测与新报告的病毒相关的人畜共患病风险。从这些综合技术中获得的信息最终将有助于我们对抗这些病原体的能力。副粘病毒附着糖蛋白和同源受体的重组表达和纯化、病毒样颗粒的制备以及针对这些糖蛋白的中和抗体（nAb）的获得/开发。副粘病毒糖蛋白单独和与细胞受体和nAb复合的晶体学分析，以提供融合前和融合后组装体的原子描述，并说明病毒进入所需的形态学变化.冷冻电子显微镜分析完整的、非致病性的病毒直系同源物，以可视化这些病毒的超微结构、其亚基糖蛋白的组装，并为整个病毒粒子的受体和抗体相互作用提供结构基础。通过体外功能分析补充病毒进入宿主细胞的结构预测决定簇。

项目成果

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil.

• DOI: 10.1126/science.abh2644
• 发表时间: 2021-05-21
• 期刊: Science (New York, N.Y.)
• 作者: Faria NR;Mellan TA;Whittaker C;Claro IM;Candido DDS;Mishra S;Crispim MAE;Sales FCS;Hawryluk I;McCrone JT;Hulswit RJG;Franco LAM;Ramundo MS;de Jesus JG;Andrade PS;Coletti TM;Ferreira GM;Silva CAM;Manuli ER;Pereira RHM;Peixoto PS;Kraemer MUG;Gaburo N Jr;Camilo CDC;Hoeltgebaum H;Souza WM;Rocha EC;de Souza LM;de Pinho MC;Araujo LJT;Malta FSV;de Lima AB;Silva JDP;Zauli DAG;Ferreira ACS;Schnekenberg RP;Laydon DJ;Walker PGT;Schlüter HM;Dos Santos ALP;Vidal MS;Del Caro VS;Filho RMF;Dos Santos HM;Aguiar RS;Proença-Modena JL;Nelson B;Hay JA;Monod M;Miscouridou X;Coupland H;Sonabend R;Vollmer M;Gandy A;Prete CA Jr;Nascimento VH;Suchard MA;Bowden TA;Pond SLK;Wu CH;Ratmann O;Ferguson NM;Dye C;Loman NJ;Lemey P;Rambaut A;Fraiji NA;Carvalho MDPSS;Pybus OG;Flaxman S;Bhatt S;Sabino EC
• 通讯作者: Sabino EC

Experimental phasing opportunities for macromolecular crystallography at very long wavelengths.

• DOI: 10.1038/s42004-023-01014-0
• 发表时间: 2023-10-12
• 期刊: COMMUNICATIONS CHEMISTRY
• 影响因子: 5.9
• 作者: El Omari, Kamel;Duman, Ramona;Mykhaylyk, Vitaliy;Orr, Christian M.;Latimer-Smith, Merlyn;Winter, Graeme;Grama, Vinay;Qu, Feng;Bountra, Kiran;Kwong, Hok Sau;Romano, Maria;Reis, Rosana I.;Vogeley, Lutz;Vecchia, Luca;Owen, C. David;Wittmann, Sina;Renner, Max;Senda, Miki;Matsugaki, Naohiro;Kawano, Yoshiaki;Bowden, Thomas A.;Moraes, Isabel;Grimes, Jonathan M.;Mancini, Erika J.;Walsh, Martin A.;Guzzo, Cristiane R.;Owens, Raymond J.;Jones, E. Yvonne;Brown, David G.;Stuart, Dave I.;Beis, Konstantinos;Wagner, Armin
• 通讯作者: Wagner, Armin

Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer.

• DOI: 10.1016/j.cell.2020.10.049
• 发表时间: 2020-12-23
• 期刊: Cell
• 影响因子: 64.5
• 作者: Avanzato VA;Matson MJ;Seifert SN;Pryce R;Williamson BN;Anzick SL;Barbian K;Judson SD;Fischer ER;Martens C;Bowden TA;de Wit E;Riedo FX;Munster VJ
• 通讯作者: Munster VJ

Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses.

• DOI: 10.1038/s41467-023-41171-3
• 发表时间: 2023-09-13
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Chapman, Nathaniel S.;Hulswit, Ruben J. G.;Westover, Jonna L. B.;Stass, Robert;Paesen, Guido C.;Binshtein, Elad;Reidy, Joseph X.;Engdahl, Taylor B.;Handal, Laura S.;Flores, Alejandra;Gowen, Brian B.;Bowden, Thomas A.;Crowe, James E., Jr.
• 通讯作者: Crowe, James E., Jr.