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Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis

A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involv...

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Autores principales: Too, Issac Horng Khit, Bonne, Isabelle, Tan, Eng Lee, Chu, Justin Jang Hann, Alonso, Sylvie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764453/
https://www.ncbi.nlm.nih.gov/pubmed/29324904
http://dx.doi.org/10.1371/journal.ppat.1006778
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author Too, Issac Horng Khit
Bonne, Isabelle
Tan, Eng Lee
Chu, Justin Jang Hann
Alonso, Sylvie
author_facet Too, Issac Horng Khit
Bonne, Isabelle
Tan, Eng Lee
Chu, Justin Jang Hann
Alonso, Sylvie
author_sort Too, Issac Horng Khit
collection PubMed
description A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications.
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spelling pubmed-57644532018-01-23 Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis Too, Issac Horng Khit Bonne, Isabelle Tan, Eng Lee Chu, Justin Jang Hann Alonso, Sylvie PLoS Pathog Research Article A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications. Public Library of Science 2018-01-11 /pmc/articles/PMC5764453/ /pubmed/29324904 http://dx.doi.org/10.1371/journal.ppat.1006778 Text en © 2018 Too et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Too, Issac Horng Khit
Bonne, Isabelle
Tan, Eng Lee
Chu, Justin Jang Hann
Alonso, Sylvie
Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title_full Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title_fullStr Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title_full_unstemmed Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title_short Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis
title_sort prohibitin plays a critical role in enterovirus 71 neuropathogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764453/
https://www.ncbi.nlm.nih.gov/pubmed/29324904
http://dx.doi.org/10.1371/journal.ppat.1006778
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