Abstract
Enterovirus 71 (EV71) causing Hand, Foot and Mouth Disease, is regarded as the most important neurotropic virus worldwide. EV71 is believed to replicate in muscles and infect motor neurons to reach the central nervous system (CNS). To further investigate the mechanisms involved, we have employed the motor neuron cell line NSC-34. NSC-34 cells were permissive to EV71 and virus production yields were strain-dependent with differential efficacy at the entry, replication and egress steps. Furthermore, unlike all the other cell lines previously reported, EV71-infected NSC-34 cells neither displayed cytopathic effect nor underwent apoptosis. Instead, autophagy was markedly up-regulated and virus-containing autophagic vacuoles were isolated from the culture supernatant, providing the first experimental evidence that EV71 can adopt a non-lytic exit pathway. Finally, the ability of EV71 to infect productively NSC-34 cells correlated with its ability to invade the CNS in vivo, supporting the relevance of NSC-34 cells to study the intrinsic neurovirulence of EV71 strains.
Highlights
Cell viability assay indicated that NSC-34 cells infected with Enterovirus 71 (EV71) at multiplicity of infection (MOI) 1 remained viable over a 96 hour-time course unlike RD, SH-SY5Y and SK-N-SH cells which displayed rapid and gradual loss in viability over time at MOI as low as 0.01 (Fig. 1b)
Infection of NSC-34 cells with S41 strain gave rise to higher virus titers than those obtained with C2 and MS strains at all the MOIs tested with a peak at 72 h.p.i. (Fig. 1c)
This observation suggests that EV71 infection profile is strain and cell line-dependent, and care should be taken in data interpretation and extrapolation to the neurovirulence potential of EV71 strains
Summary
Presence of infectious virus particles in the culture supernatant from EV71-infected NSC-34 cells was readily detected, indicating that the lack of CPE and cell death observed is not due to the inability of the virus to enter and/or replicate effectively in these cells (Fig. 1c). This is in contrast with the kinetic profiles obtained upon infection with the whole virus, where virus titers measured in the culture supernatant of S41-infected NSC-34 cells (MOI 1 and above) were significantly higher than those measured in C2-infected cells at all the time points studied (Fig. 1).
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