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Model System for the Formation of Tick-Borne Encephalitis Virus Replication Compartments without Viral RNA Replication
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
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2019 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 93, no 18, article id e00292-19Article in journal (Refereed) Published
Abstract [en]

Flavivirus is a positive-sense, single-stranded RNA viral genus, with members causing severe diseases in humans such as tick-borne encephalitis, yellow fever, and dengue fever. Flaviviruses are known to cause remodeling of intracellular membranes into small cavities, where replication of the viral RNA takes place. Nonstructural (NS) proteins are not part of the virus coat and are thought to participate in the formation of these viral replication compartments (RCs). Here, we used tick-borne encephalitis virus (TBEV) as a model for the flaviviruses and developed a stable human cell line in which the expression of NS proteins can be induced without viral RNA replication. The model system described provides a novel and benign tool for studies of the viral components under controlled expression levels. We show that the expression of six NS proteins is sufficient to induce infection-like dilation of the endoplasmic reticulum (ER) and the formation of RC-like membrane invaginations. The NS proteins form a membrane-associated complex in the ER, and electron tomography reveals that the dilated areas of the ER are closely associated with lipid droplets and mitochondria. We propose that the NS proteins drive the remodeling of ER membranes and that viral RNA, RNA replication, viral polymerase, and TBEV structural proteins are not required. IMPORTANCE TBEV infection causes a broad spectrum of symptoms, ranging from mild fever to severe encephalitis. Similar to other flaviviruses, TBEV exploits intracellular membranes to build RCs for viral replication. The viral NS proteins have been suggested to be involved in this process; however, the mechanism of RC formation and the roles of individual NS proteins remain unclear. To study how TBEV induces membrane remodeling, we developed an inducible stable cell system expressing the TBEV NS polyprotein in the absence of viral RNA replication. Using this system, we were able to reproduce RC-like vesicles that resembled the RCs formed in flavivirus-infected cells, in terms of morphology and size. This cell system is a robust tool to facilitate studies of flavivirus RC formation and is an ideal model for the screening of antiviral agents at a lower biosafety level.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY , 2019. Vol. 93, no 18, article id e00292-19
Keywords [en]
Flaviviridae, Flp-In cell line, NS4B, flavivirus, replication compartment, replication vesicles, tick-borne cephalitis virus
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-164506DOI: 10.1128/JVI.00292-19ISI: 000483427300003PubMedID: 31243132OAI: oai:DiVA.org:umu-164506DiVA, id: diva2:1372322
Available from: 2019-11-22 Created: 2019-11-22 Last updated: 2019-11-22Bibliographically approved

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Yau, Wai-LokNguyen-Dinh, VanLarsson, ElinLindquist, RichardÖverby, Anna K.Lundmark, Richard

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Yau, Wai-LokNguyen-Dinh, VanLarsson, ElinLindquist, RichardÖverby, Anna K.Lundmark, Richard
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Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)Department of Integrative Medical Biology (IMB)Section of Virology
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