Abstract
Enterovirus 71 (EV71) is one of the main causative agents of foot, hand and mouth disease. Its infection usually causes severe central nervous system diseases and complications in infected infants and young children. In the present study, we demonstrated that EV71 infection caused the rearrangement of vimentin in human astrocytoma cells. The rearranged vimentin, together with various EV71 components, formed aggresomes-like structures in the perinuclear region. Electron microscopy and viral RNA labeling indicated that the aggresomes were virus replication sites since most of the EV71 particles and the newly synthesized viral RNA were concentrated here. Further analysis revealed that the vimentin in the virus factories was serine-82 phosphorylated. More importantly, EV71 VP1 protein is responsible for the activation of calmodulin-dependent protein kinase II (CaMK-II) which phosphorylated the N-terminal domain of vimentin on serine 82. Phosphorylation of vimentin and the formation of aggresomes were required for the replication of EV71 since the latter was decreased markedly after phosphorylation was blocked by KN93, a CaMK-II inhibitor. Thus, as one of the consequences of CaMK-II activation, vimentin phosphorylation and rearrangement may support virus replication by playing a structural role for the formation of the replication factories. Collectively, this study identified the replication centers of EV71 in human astrocyte cells. This may help us understand the replication mechanism and pathogenesis of EV71 in human.
Highlights
Enterovirus 71 (EV71) is a single-stranded RNA icosahedral virus 30 nm in diameter belonging to the genus Enterovirus within the Picornaviridae family
The results showed that EV71 could directly infect U251 human astrocytoma cells and numerous detached, round and floating cells displayed the signs of cytopathocity could be detected 48 hours postinfection (Fig. 1A)
When the phosphorylation of vimentin was blocked by KN93, the VP1 was detected throughout the cytoplasm instead of being assembled in the perinuclear region (Fig. 6C). These results indicated that the activation of calmodulin-dependent protein kinase II (CaMK-II) and the vimentin rearrangement during EV71 infection was mostly attributed to VP1 protein expression, while the formation of aggresomes, the putative virus replication centers, needed the participation of other viral components
Summary
Enterovirus 71 (EV71) is a single-stranded RNA icosahedral virus 30 nm in diameter belonging to the genus Enterovirus within the Picornaviridae family. EV71 infections are usually accompanied by severe neurological complications such as aseptic meningitis, acute flaccid paralysis, encephalitis and other rarer manifestations [2], [3]. These neurological complications can sometimes be fatal and neurogenic pulmonary edema is thought to be the main disease process in fatal cases. It has been postulated that overwhelming virus replication, combining with the induction of toxic inflammatory cytokines and cellular immunity resulting from tissue damage, are possibly the process of pathogenesis [4], [5]. The initial viral illness often is self-limited, EV71 infection may result in long term neurologic and psychiatric effects on the central nervous system (CNS) in children. Available treatments for EV71 infection and HFMD are limited as there is currently no effective chemoprophylaxis or vaccination for HFMD or EV71 infection
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