Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody

Xu, Longfa; Zheng, Qingbing; Li, Shaowei; He, Maozhou; Wu, Yangtao; Li, Yongchao; Zhu, Rui; Yu, Hai; Hong, Qiyang; Jiang, Jie; Li, Zizhen; Li, Shuxuan; Zhao, Huan; Yang, Lijie; Hou, Wangheng; Wang, Wei; Ye, Xiangzhong; Zhang, Jun; Baker, Timothy S.; Cheng, Tong; Zhou, Z. Hong; Yan, Xiaodong; Xia, Ningshao

doi:10.1038/s41467-017-00477-9

Cited by 70 publications

(81 citation statements)

References 60 publications

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“…The structures both of pentamers and of the inside-out empty capsid show no density corresponding to VP4, suggesting that VP4 is essential for the correct procapsid assembly. A different situation is observed in the case of EV71 (58) and coxsackieviruses (23), where VP0 is not cleaved in the procapsid and no density corresponding to the VP4 region is observed, indicating that this region is not ordered. A possible explanation could be that the cleavage of VP0 in the absence of the viral RNA would lead to the dissociation of VP4 from the capsid.…”

Section: Discussionmentioning

confidence: 87%

“…However, the procapsids are much less well studied. Procapsid structures have been solved by cryo-EM or X-ray crystallography for enteroviruses, such as PV (19), EV71 (21), rhinovirus (22), and coxsackieviruses (20,23). All these structures show an unexpanded capsid with an uncleaved VP0 arranged in a conformation different from that of the final configuration of VP2 and VP4 in the mature capsid.…”

Section: Discussionmentioning

confidence: 99%

“…For members of the Enterovirus family, the presence of a late-entry intermediate empty capsid with a sedimentation coefficient of 80S is well documented as a final stage of the genome uncoating process (18). More puzzling is the presence of a procapsid, having a sedimentation coefficient of 75S, observed in enteroviruses (19)(20)(21)(22)(23), hepatoviruses (24), and aphthoviruses (25). Several roles have been proposed: as a strategy for the storage of pentamers to be used later for full virion assembly, as a way of deterring the recognition by neutralizing antibodies, as a procapsid in which the RNA will be further packaged, or as a simple dead-end during viral assembly.…”

mentioning

confidence: 99%

“…The existence of procapsids for members of other genera of the Picornaviridae is elusive, since they are far less abundant and very unstable (26). Procapsids have been reported for several enteroviruses, such as poliovirus (PV) (19), rhinovirus (22), enterovirus 71 (EV71) (21), and coxsackieviruses (20,23), as well as for foot-and-mouth disease virus (FMDV) (27) and hepatitis A virus (HAV) (24). No empty particles of any type have been reported for cardioviruses, the closest structural relatives to senecavirus.…”

mentioning

confidence: 99%

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Cryo-Electron Microscopy Structure of Seneca Valley Virus Procapsid

Strauß

Jayawardena

Sun

et al. 2018

J Virol

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Seneca Valley Virus, like some other members of the picornaviridae, forms naturally occurring empty capsids, known as procapsids. The procapsid has the same antigenicity as the full virion, so they present an interesting possibility for the formation of stable virus-like particles. Interestingly, although SVV is a livestock pathogen, it has also been found to preferentially infect tumour cells, and is being explored for use as a therapeutic agent in the treatment of small cell lung cancers. Here we used cryo-electron microscopy to investigate the procapsid structure and describe the transition of capsid protein VP0 to the cleaved forms of VP4 and VP2. We show that the SVV receptor binds the procapsid, as evidence of its native antigenicity. In comparing the procapsid structure to that of the full virion, we also show that a cage of RNA serves to stabilize the inside surface of the virus, thereby making it more acid-stable.Viruses are extensively studied to help us understand infection and disease. One of the by-products of some virus infections are the naturally occurring empty virus capsids (containing no genome), termed procapsids, whose function remains unclear. Here we investigate the structure and formation of the procapsids of Seneca Valley Virus, to better understand how they form, what causes them to form, how they behave, and how we can make use of them. One potential benefit of this work is the modification of the procapsid to develop it for targeted delivery of therapeutics or to make a stable vaccine against SVV, which could be of great interest to the agricultural industry.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cryo-Electron Microscopy Structure of Seneca Valley Virus Procapsid

Strauß

Jayawardena

Sun

et al. 2018

J Virol

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“…While our paper was under review, the structures of the CVA6 procapsid and A particle were published (66).…”

Section: Addendummentioning

confidence: 99%

A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-Like Particles

Chen

Zhang

Zhou

et al. 2018

J Virol

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Coxsackievirus A6 (CVA6) has recently emerged as one of the predominant causative agents of hand, foot, and mouth disease (HFMD). The structure of the CVA6 mature viral particle has not been solved thus far. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 represent a promising CVA6 vaccine candidate. Here, we report the first cryo-electron microscopy (cryo-EM) structure of the CVA6 VLP at 3.0-Å resolution. The CVA6 VLP exhibits the characteristic features of enteroviruses but presents an open channel at the 2-fold axis and an empty, collapsed VP1 pocket, which is broadly similar to the structures of the enterovirus 71 (EV71) VLP and coxsackievirus A16 (CVA16) 135S expanded particle, indicating that the CVA6 VLP is in an expanded conformation. Structural comparisons reveal that two common salt bridges within protomers are maintained in the CVA6 VLP and other viruses of the genus, implying that these salt bridges may play a critical role in enteroviral protomer assembly. However, there are apparent structural differences among the CVA6 VLP, EV71 VLP, and CVA16 135S particle in the surface-exposed loops and C termini of subunit proteins, which are often antigenic sites for enteroviruses. By immunological assays, we identified two CVA6-specific linear B-cell epitopes (designated P42 and P59) located at the GH loop and the C-terminal region of VP1, respectively, in agreement with the structure-based prediction of antigenic sites. Our findings elucidate the structural basis and important antigenic sites of the CVA6 VLP as a strong vaccine candidate and also provide insight into enteroviral protomer assembly. Coxsackievirus A6 (CVA6) is becoming one of the major pathogens causing hand, foot, and mouth disease (HFMD), leading to significant morbidity and mortality in children and adults. However, no vaccine is currently available to prevent CVA6 infection. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 are a promising CVA6 vaccine candidate. Here, we present a 3.0-Å structure of the CVA6 VLP determined by cryo-electron microscopy. The overall architecture of the CVA6 VLP is similar to those of the expanded structures of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), but careful structural comparisons reveal significant differences in the surface-exposed loops and C termini of each capsid protein of these particles. In addition, we identified two CVA6-specific linear B-cell epitopes and mapped them to the GH loop and the C-terminal region of VP1, respectively. Collectively, our findings provide a structural basis and important antigenic information for CVA6 VLP vaccine development.

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Molecular epidemiology of coxsackievirus A6 derived from hand, foot, and mouth disease in Fukuoka between 2013 and 2017

Yoshitomi

Ashizuka

Ichihara

et al. 2018

Journal of Medical Virology

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Coxsackievirus (CV)-A6 has been the primary causative agent of hand, foot, and mouth disease (HFMD) in Japan since 2011. In Fukuoka, CV-A6-associated HFMD caused epidemics in 2013, 2015, and 2017. This paper reports the genetic characteristics of the CV-A6 entire viral protein 1 (VP1) derived from patients with HFMD in Fukuoka between 2013 and 2017. CV-A6 was detected in 105 of 280 clinical specimens, and the entire VP1 sequences could be analyzed for 90 of the 105 specimens. Phylogenetic analysis revealed that the CV-A6 strains were classified into clade A and subgrouped into subclade A3 or subclade A4. Each subclade strain carried amino acid substitutions in the presumed DE and GH loops of the VP1, and no amino acid substitutions were identified as deleterious to the protein function. No significant difference was found in the clinical symptoms between the genetic subclades using statistical analyses. In conclusion, this study clarified the genetic diversity of CV-A6 in Fukuoka from 2013 to 2017. The emergence of the CV-A6 strains was classified into derived new subclades based on phylogenetic analysis of the VP1 gene that may cause CV-A6-associated HFMD epidemics approximately every 2 years.

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Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody

Cited by 70 publications

References 60 publications

Cryo-Electron Microscopy Structure of Seneca Valley Virus Procapsid

Cryo-Electron Microscopy Structure of Seneca Valley Virus Procapsid

A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-Like Particles

Molecular epidemiology of coxsackievirus A6 derived from hand, foot, and mouth disease in Fukuoka between 2013 and 2017

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