Qingbing Zheng / Rui Zhu / Zhichao Yin / Longfa Xu / Hui Sun / Hai Yu / Yuanyuan Wu / Yichao Jiang / Qiongzi Huang / Yang Huang / Dongqing Zhang / Liqin Liu / Hongwei Yang / Maozhou He / Zhenhong Zhou / Yanan Jiang / Zhenqin Chen / Huan Zhao / Yuqiong Que / Zhibo Kong / Lizhi Zhou / Tingting Li / Jun Zhang / Wenxin Luo / Ying Gu / Tong Cheng / Shaowei Li / Ningshao Xia /
PubMed Abstract
Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. ...Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. We characterize the binding and therapeutic efficacies of three CVB1-specific neutralizing antibodies (nAbs) identified for their ability to inhibit host receptor engagement. High-resolution cryo-EM structures showed that these antibodies recognize different epitopes but with an overlapping region in the capsid VP2 protein and specifically the highly variable EF loop. Moreover, they perturb capsid-receptor interactions by binding various viral particle forms. Antibody combinations achieve synergetic neutralization via a stepwise capsid transition and virion disruption, indicating dynamic changes in the virion in response to multiple nAbs targeting the receptor-binding site. Furthermore, this three-antibody cocktail protects against lethal challenge in neonatal mice and limits pancreatitis and viral replication in a non-obese diabetic mouse model. These results illustrate the utility of nAbs for rational design of therapeutics against picornaviruses such as CVB.
EMDB-32967, PDB-7x2g: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb nAb 2E6 (CVB1-E:2E6) Method: EM (single particle) / Resolution: 3.58 Å
EMDB-32968, PDB-7x2i: Cryo-EM structure of Coxsackievirus B1 pre-A particle in complex with nAb 2E6 (CVB1-pre-A:2E6) Method: EM (single particle) / Resolution: 3.29 Å
EMDB-32969, PDB-7x2o: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 2E6 (CVB1-M:2E6) Method: EM (single particle) / Resolution: 3.15 Å
EMDB-32970, PDB-7x2t: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (CVB1-M:8A10) Method: EM (single particle) / Resolution: 3.69 Å
EMDB-32973, PDB-7x2w: Cryo-EM structure of Coxsackievirus B1 pre-A particle in complex with nAb 8A10 (CVB1-pre-A:8A10) Method: EM (single particle) / Resolution: 3.24 Å
EMDB-32979, PDB-7x35: Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 8A10 (CVB1-A:8A10) Method: EM (single particle) / Resolution: 3.19 Å
EMDB-32980, PDB-7x37: Cryo-EM structure of Coxsackievirus B1 A particle in complex with nAb 2E6 (CVB1-A:2E6) Method: EM (single particle) / Resolution: 3.31 Å
EMDB-32981, PDB-7x38: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 8A10 (CVB1-E:8A10) Method: EM (single particle) / Resolution: 3.52 Å
EMDB-32983, PDB-7x3c: Cryo-EM structure of Coxsackievirus B1 muture virion in complex with nAbs 8A10 and 5F5 (CVB1-M:8A10:5F5) Method: EM (single particle) / Resolution: 3.03 Å
EMDB-32984, PDB-7x3d: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 9A3 (CVB1-M:9A3) Method: EM (single particle) / Resolution: 3.48 Å
EMDB-32985, PDB-7x3e: Cryo-EM structure of Coxsackievirus B1 pre-A-particle in complex with nAb 9A3 (CVB1-pre-A:9A3) Method: EM (single particle) / Resolution: 3.44 Å
EMDB-32986, PDB-7x3f: Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 9A3 (CVB1-A:9A3) Method: EM (single particle) / Resolution: 3.52 Å
EMDB-32997, PDB-7x3y: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (CVB1-E:9A3) Method: EM (single particle) / Resolution: 3.32 Å
EMDB-32998, PDB-7x40: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 2E6) Method: EM (single particle) / Resolution: 3.02 Å
EMDB-32999, PDB-7x42: Cryo-EM structure of Coxsackievirus B1 pre-A-particle in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 2E6) Method: EM (single particle) / Resolution: 3.88 Å
EMDB-33000, PDB-7x46: Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10 and 2E6) Method: EM (single particle) / Resolution: 3.85 Å
EMDB-33001, PDB-7x47: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10 and 2E6) Method: EM (single particle) / Resolution: 3.66 Å
EMDB-33002, PDB-7x49: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 9A3) Method: EM (single particle) / Resolution: 3.13 Å
EMDB-33003: Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3) Method: EM (single particle) / Resolution: 4.01 Å
EMDB-33004, PDB-7x4k: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3) Method: EM (single particle) / Resolution: 3.82 Å
EMDB-33005, PDB-7x4m: Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10, 2E6 and 9A3) Method: EM (single particle) / Resolution: 3.34 Å
EMDB-33006: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10, 2E6 and 9A3) Method: EM (single particle) / Resolution: 4.18 Å
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