Abstract
Infection with enterovirus-A71 (EV-A71) can cause hand-foot-mouth disease associated with fatal neurological complications. The host response to EV-A71 has not yet been fully elucidated, thus, hampering the development of a precise therapeutic approach. A nonstructural 2B protein of EV-A71 has been reported to involve with calcium dysregulation and apoptosis induction in human neuroblastoma SH-SY5Y cells. However, the molecular mechanism has not been delineated. To address this, comprehensive study of the gene expression from SH-SY5Y cells transfected with EV-A71 2B was carried out by RNA sequencing and transcriptomic analysis. It was found that the signature of the upregulated genes of SH-SY5Y cells expressing EV-A71 2B involved the Ca2+-related signaling pathways participating gene expression, inflammatory response, apoptosis, and long-term potentiation of the neuron. Protein–protein interaction network analysis revealed that the products encoded by CCL2, RELB, BIRC3, and TNFRSF9 were the most significant hub proteins in the network. It indicated that EV-A71 2B protein might play a role in immunopathogenesis of the central nervous system (CNS) which probably associated with the non-canonical NF-κB pathway. The data suggest that transcriptomic profiling can provide novel information source for studying the neuropathogenesis of EV-A71 infection leading to development of an effective therapeutic measure for CNS complications.
Highlights
Infection with enterovirus-A71 (EV-A71) can cause hand-foot-mouth disease associated with fatal neurological complications
Emerging knowledge indicates that dysregulated calcium homeostasis in neuronal cells could trigger complex and diverse signal transduction pathways that lead to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases[8,9]
It indicated the involvement of ER-mitochondrial interaction triggered by mobilization of Ca2+ between ER and mitochondria leading to disturbance of normal functions of the organelles and activation of caspasedependent intrinsic apoptosis pathways in the EV-A71 2B transfected SH-SY5Y cells
Summary
Infection with enterovirus-A71 (EV-A71) can cause hand-foot-mouth disease associated with fatal neurological complications. It was found that the signature of the upregulated genes of SH-SY5Y cells expressing EV-A71 2B involved the Ca2+-related signaling pathways participating gene expression, inflammatory response, apoptosis, and longterm potentiation of the neuron. The exact molecular mechanisms or pathways that involve the neuropathogenesis have not been elucidated resulting in dampening the development of therapeutic and preventive strategies for fatal complications of the EV-A71 infection. In the case of EV-A71 infection, our previous publication has reported that the nonstructural 2B protein of the EV-A71 could increase cytosolic Ca2+ at 6 h post-transfection and induce apoptosis in the transfected human neuroblastoma SH-SY5Y cells. It indicated the involvement of ER-mitochondrial interaction triggered by mobilization of Ca2+ between ER and mitochondria leading to disturbance of normal functions of the organelles and activation of caspasedependent intrinsic apoptosis pathways in the EV-A71 2B transfected SH-SY5Y cells. The gained knowledge will provide new insight into the underlying mechanisms of the virus-host interactions leading to neuropathogenesis of the EV-A71 infection and the target candidates for therapeutics
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