Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice

English version

Autoři: Han Kang Tee ^aff001; Chee Wah Tan ^aff001; Thinesshwary Yogarajah ^aff001; Michelle Hui Pheng Lee ^aff001; Hann Juang Chai ^aff002; Nur Aziah Hanapi ^aff003; Siti R. Yusof ^aff003; Kien Chai Ong ^aff004; Vannajan Sanghiran Lee ^aff005; I-Ching Sam ^aff001; Yoke Fun Chan ^aff001
Působiště autorů: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia ^aff001; Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia ^aff002; Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia ^aff003; Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia ^aff004; Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia ^aff005
Vyšlo v časopise: Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive EV-A71 virulence in mice. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1007863
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007863

Souhrn

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 brain virus antigens in mice, 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 heparin-rich 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.

Klíčová slova:

Electrostatics – Heparin – Mouse models – Skeletal muscles – Viral packaging – Viral replication – Viremia – Neurovirulence

Zdroje

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