Shimizu, Hiroyuki and Tee, Han Kang and Tan, Chee Wah and Yogarajah, Thinesshwary and Lee, Michelle Hui Pheng and Chai, Hann Juang and Hanapi, Nur Aziah and Yusof, Siti R. and Ong, Kien Chai and Lee, Vannajan Sanghiran and Sam, I-Ching and Chan, Yoke Fun (2019) Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice. PLoS Pathogens, 15 (11). e1007863. ISSN 1553-7374, DOI https://doi.org/10.1371/journal.ppat.1007863.
Full text not available from this repository.Abstract
Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP2-149, VP1-145 and VP1-244. We investigate how these amino acids alter heparin-binding phenotype and shapes EV-A71 virulence in one-day old mice. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 149K/98E/145Q, termed KEQ) to generate KKQ, KKE, KEE, IEE and IEQ variants. We demonstrated that the weak heparin-binder IEE was highly lethal in mice. The initially strong heparin-binding IEQ variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased virus antigens in mice brain, with subsequent high virulence. IEE and IEQ-244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of IEQ attenuated the virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-fold axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparinrich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching between heparin-binding and weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71. © 2019 Public Library of Science. All rights reserved.
| Item Type: | Article |
|---|---|
| Funders: | UNSPECIFIED |
| Uncontrolled Keywords: | adaptation; animal experiment; animal tissue; binding affinity; computer model; controlled study; Enterovirus A71; gene mutation; gene sequence; heparin binding; human; human cell; immunohistochemistry; molecular docking; mouse; nerve cell; nonhuman; pathogenesis; phenotype; polymerase chain reaction; protein binding; RD cell line; real time polymerase chain reaction; rhabdomyosarcoma cell line; RNA extraction; Sanger sequencing; site directed mutagenesis; static electricity; viremia; virus strain; virus virulence |
| Subjects: | Q Science > Q Science (General) Q Science > QD Chemistry R Medicine |
| Divisions: | Faculty of Medicine Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 23 Dec 2019 01:32 |
| Last Modified: | 23 Dec 2019 01:32 |
| URI: | http://eprints.um.edu.my/id/eprint/23268 |
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