IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The...

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Autores principales:	Veronika J. M. Breitkopf, Gerhard Dobler, Peter Claus, Hassan Y. Naim, Imke Steffen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	flavivirus tick-borne encephalitis virus Langat virus viral replication ER stress unfolded protein response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/435a7a686d3b456e9f0a1edd3300a685
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spelling	oai:doaj.org-article:435a7a686d3b456e9f0a1edd3300a6852021-11-25T19:12:57ZIRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner10.3390/v131121641999-4915https://doaj.org/article/435a7a686d3b456e9f0a1edd3300a6852021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2164https://doaj.org/toc/1999-4915Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The IRE1 pathway has been hypothesized to support flavivirus replication by increasing protein and lipid biogenesis. Here, we investigated the role of the UPR in TBFV infection in human astrocytes, neuronal and intestinal cell lines that had been infected with tick-borne encephalitis virus (TBEV) strains Neudoerfl and MucAr-HB-171/11 as well as Langat virus (LGTV). Both TBEV strains replicated better than LGTV in central nervous system (CNS) cells. TBEV strain MucAr-HB-171/11, which is associated with gastrointestinal symptoms, replicated best in intestinal cells. All three viruses activated the inositol-requiring enzyme 1 (IRE1) pathway via the X-box binding protein 1 (XBP1). Interestingly, the neurotropic TBEV strain Neudoerfl induced a strong upregulation of XBP1 in all cell types, but with faster kinetics in CNS cells. In contrast, TBEV strain MucAr-HB-171/11 failed to activate the IRE1 pathway in astrocytes. The low pathogenic LGTV led to a mild induction of IRE1 signaling in astrocytes and intestinal cells. When cells were treated with IRE1 inhibitors prior to infection, TBFV replication in astrocytes was significantly reduced. This confirms a supporting role of the IRE1 pathway for TBFV infection in relevant viral target cells and suggests a correlation between viral tissue tropism and the cell-type dependent induction of the unfolded protein response.Veronika J. M. BreitkopfGerhard DoblerPeter ClausHassan Y. NaimImke SteffenMDPI AGarticleflavivirustick-borne encephalitis virusLangat virusviral replicationER stressunfolded protein responseMicrobiologyQR1-502ENViruses, Vol 13, Iss 2164, p 2164 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	flavivirus tick-borne encephalitis virus Langat virus viral replication ER stress unfolded protein response Microbiology QR1-502
spellingShingle	flavivirus tick-borne encephalitis virus Langat virus viral replication ER stress unfolded protein response Microbiology QR1-502 Veronika J. M. Breitkopf Gerhard Dobler Peter Claus Hassan Y. Naim Imke Steffen IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
description	Tick-borne flaviviruses (TBFV) can cause severe neurological complications in humans, but differences in tissue tropism and pathogenicity have been described for individual virus strains. Viral protein synthesis leads to the induction of the unfolded protein response (UPR) within infected cells. The IRE1 pathway has been hypothesized to support flavivirus replication by increasing protein and lipid biogenesis. Here, we investigated the role of the UPR in TBFV infection in human astrocytes, neuronal and intestinal cell lines that had been infected with tick-borne encephalitis virus (TBEV) strains Neudoerfl and MucAr-HB-171/11 as well as Langat virus (LGTV). Both TBEV strains replicated better than LGTV in central nervous system (CNS) cells. TBEV strain MucAr-HB-171/11, which is associated with gastrointestinal symptoms, replicated best in intestinal cells. All three viruses activated the inositol-requiring enzyme 1 (IRE1) pathway via the X-box binding protein 1 (XBP1). Interestingly, the neurotropic TBEV strain Neudoerfl induced a strong upregulation of XBP1 in all cell types, but with faster kinetics in CNS cells. In contrast, TBEV strain MucAr-HB-171/11 failed to activate the IRE1 pathway in astrocytes. The low pathogenic LGTV led to a mild induction of IRE1 signaling in astrocytes and intestinal cells. When cells were treated with IRE1 inhibitors prior to infection, TBFV replication in astrocytes was significantly reduced. This confirms a supporting role of the IRE1 pathway for TBFV infection in relevant viral target cells and suggests a correlation between viral tissue tropism and the cell-type dependent induction of the unfolded protein response.
format	article
author	Veronika J. M. Breitkopf Gerhard Dobler Peter Claus Hassan Y. Naim Imke Steffen
author_facet	Veronika J. M. Breitkopf Gerhard Dobler Peter Claus Hassan Y. Naim Imke Steffen
author_sort	Veronika J. M. Breitkopf
title	IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
title_short	IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
title_full	IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
title_fullStr	IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
title_full_unstemmed	IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner
title_sort	ire1-mediated unfolded protein response promotes the replication of tick-borne flaviviruses in a virus and cell-type dependent manner
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/435a7a686d3b456e9f0a1edd3300a685
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IRE1-Mediated Unfolded Protein Response Promotes the Replication of Tick-Borne Flaviviruses in a Virus and Cell-Type Dependent Manner

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