Fig 9. Hypothesized model of EV-A71 heparin-dependent pathogenesis in human.

Three major factors are responsible for EV-A71 virulence determination, namely virus entry, peripheral dissemination and neuroinvasion. (A) Both strong and weak heparin binders infect humans at the same rate, using the same inoculation route and receptor. (B) Viremia is established upon virus entry. Strong heparin binders are more readily removed from the blood circulation by binding to peripheral tissues due to their high affinity to heparin. Meanwhile, weak heparin binders give rise to higher viremia with better dissemination to other organs. (C) Neuroinvasion occurs when virus travels from peripheral motor nerves to the CNS via retrograde axonal transport.