Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1007863
Title: Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice
Authors: Tee, Han Kang
Tan, Chee Wah 
Yogarajah, Thinesshwary 
Lee, Michelle Hui Pheng
Chai, Hann Juang
Hanapi, Nur Aziah
Yusof, Siti R
Ong, Kien Chai
Lee, Vannajan Sanghiran
Sam, I-Ching
Chan, Yoke Fun
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
CAPSID PROTEIN VP1
SELECTIN GLYCOPROTEIN LIGAND-1
ENCEPHALITIS-VIRUS
MOUSE ADAPTATION
SULFATE BINDING
JAPANESE ENCEPHALITIS
E2 GLYCOPROTEIN
SINGLE MUTATION
MOUTH-DISEASE
71 INFECTION
Issue Date: Nov-2019
Publisher: PUBLIC LIBRARY SCIENCE
Citation: Tee, Han Kang, Tan, Chee Wah, Yogarajah, Thinesshwary, Lee, Michelle Hui Pheng, Chai, Hann Juang, Hanapi, Nur Aziah, Yusof, Siti R, Ong, Kien Chai, Lee, Vannajan Sanghiran, Sam, I-Ching, Chan, Yoke Fun (2019-11). Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice. PLOS PATHOGENS 15 (11). ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1007863
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.
Source Title: PLOS PATHOGENS
URI: https://scholarbank.nus.edu.sg/handle/10635/247888
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1007863
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