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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 |
Appears in Collections: | Staff Publications Elements |
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