The Remodeling of the Cytoplasm by Dengue Virus

Special Article - Dengue Virus Infection

J Bacteriol Mycol. 2016; 3(5): 1039.

The Remodeling of the Cytoplasm by Dengue Virus

Chatel-Chaix L*

Institut National de la Recherche Scientifique, Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, H7V 1B7, Québec, Canada

*Corresponding author: Laurent Chatel-Chaix, Institut National de la Recherche Scientifique, Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, H7V 1B7, Québec, Canada

Received: November 22, 2016; Accepted: December 16, 2016; Published: December 19, 2016


Infection with Dengue Virus (DENV) causes the most prevalent arthropodborne viral disease worldwide. Since there are no antivirals available, there is an urgent medical need to discover novel therapeutic targets, implying a better understanding of the cellular and molecular events governing DENV life cycle. Following infection, DENV induces a massive remodeling of the cytoplasm including the endoplasmic reticulum from which DENV replication factories are formed. In addition, DENV alters the morphology of other organelles such as mitochondria to hijack their functions and to create a cellular environment favorable to viral replication. This review summarizes our current knowledge about the cytoplasmic remodeling activities of DENV.

Keywords: Dengue virus; Replication factories; Autophagy; Mitochondria; Innate immunity


CM: Convoluted Membranes; DENV: Dengue Virus; DRP1: Dynamin-Related Protein-1; dsRNA : Double-stranded RNA; eIF2α: Eukaryotic initiation factor 2 alpha; ER: Endoplasmic Reticulum; G3BP: Ras-GAP SH3-domain-Binding Protein; IFN: Interferon; IP3R: Inositol Trisphosphate Receptor; GRP75: Glucose- Regulated Protein 75 Kda; ISG: Interferon Stimulated Genes; LC3: Microtubule associated protein 1 Light Chain 3; LD: Lipid Droplets; MAM: Mitochondria-Associated Membranes; MDA5: Melanoma Differentiation-Associated Gene 5; MFN2: Mitofusin-2; mRNA: messenger RNA; PKR : Protein Kinase R; RF : Replication Factories; RIG-I: Retinoic Acid-Inducible Gene-I; sfRNA: Sub-flaviviral RNA; SG: Stress Granules; Spautin1: Specific And Potent Autophagy Inhibitor 1; STING: Stimulator of Interferon Genes; TCA: Tri Carboxylic Acid; TIA-1: T-Cell Intracellular Antigen Protein-1; TIAR: T-Cell Restricted Intracellular Antigen 1-Related Protein; VB: Virus Bags; VDAC-1: Voltage-Dependent Anion Receptor-1; VP: Vesicle Packets; vRNA: Viral RNA; WNV: West Nile Virus; YFV: Yellow Fever Virus; ZIKV : Zika Virus


Infection with Dengue Virus (DENV) causes the most prevalent arthropod-borne viral disease worldwide. Humans are infected by the bite of female Aedes mosquitoes (Aedes aegypti and Aedes albopictus) during their blood meal [1]. Occurring in over 100 countries, the prevalence of this emerging disease has increased by 30 fold over the last 50 years. It has been estimated that 400 million individuals are infected annually [2], among which 25% are reported to develop symptoms typical of dengue fever. In some cases, the infection causes dengue hemorrhagic fever, dengue shock syndrome and eventually death. A prophylactic tetravalent vaccine has been recently developed by Sanofi (Dengvaxia®) [3]. However, it provides limited efficacy and has been approved only in 6 countries. Importantly, despite current efforts, antiviral drugs are still not available. Hence, DENV infection represents an important global burden and there is an urgent medical need to develop novel therapeutic approaches. This has been hampered by the fact that our knowledge about the molecular events governing DENV life cycle remains limited.

DENV is an enveloped positive-strand RNA virus belonging to the Flavivirus genus within the Flaviviridae virus family [4]. In addition to DENV, flaviviruses comprise over 70 members including Yellow Fever Virus (YFV), Zika Virus (ZIKV) and West Nile Virus (WNV). Following receptor-mediated endocytosis and envelop fusion, the unique DENV RNA species, namely the viral genome (vRNA) is uncoated and released into the cytosol to be translated at the Endoplasmic Reticulum (ER). The vRNA contains one single open reading frame which encodes a viral transmembrane polyprotein. It is co- and post-translationally processed by cellular and viral proteases, generating 10 mature viral proteins. The nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) are indispensable for vRNA replication. Notably, NS5, through its RNA-dependent RNA polymerase and methyltransferase enzymatic activities, replicates and caps the vRNA. NS3 with its co-factor NS2B harbors a protease activity responsible for the processing of the polyprotein at the junctions located on the cytosolic side of the ER. In addition, NS3 also contains RNA helicase, NTPase and RNA triphosphatase activities, all indispensable for efficient vRNA replication. The structural proteins capsid (C), prM and envelop (E) are responsible for assembling and enveloping novel viral particles which are immature. During egress through the secretory pathway, viral particles undergo maturation and become infectious through conformational changes following the processing of prM by cellular furin [4-7].

Like most positive strand RNA viruses [6], DENV induces massive rearrangements of the ER in the infected cell to create organellelike membranous structures generically called Replication Factories (RF). These ultrastructures showing remarkable morphologies are believed to be required for the DENV life cycle. The viral and cellular determinants of DENV RF morphogenesis remain enigmatic. In the recent years, numerous studies have revealed that other cytoplasmic organelles than ER are also hijacked by DENV. The co-opting of their activities by DENV is often associated with noticeable changes in their morphologies. This cytoplasmic remodeling by DENV creates a cellular environment which is optimal not only for virus replication but also for evading antiviral defenses such as innate immunity.

DENV Replication Factories

Shortly after infection, DENV induces massive ER reorganization to generate three typical ultrastructures (Figure 1, left panel) which can be readily detected by Transmission Electron Microscopy (TEM).

Citation: Chatel-Chaix L. The Remodeling of the Cytoplasm by Dengue Virus. J Bacteriol Mycol. 2016; 3(5): 1039. ISSN : 2471-0172