Recent Developments in Understanding Dengue Virus Replication

Urcuqui-Inchima, Silvio; Patiño, Claudia; Torres, Silvia; Haenni, Anne‐Lise; Díaz, Francisco Javier

doi:10.1016/b978-0-12-385034-8.00001-6

Cited by 44 publications

(28 citation statements)

References 196 publications

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“…The molecular mechanisms of DENV replication can affect the clinical outcomes (35). It is apparent that an understanding of the DENV replication cycle will require characterization of the physical and functional interactions of the proteins that form the DENV RC, including unidentified host proteins.…”

Section: Discussionmentioning

confidence: 99%

Cellular Vimentin Regulates Construction of Dengue Virus Replication Complexes through Interaction with NS4A Protein

Teo

Chu

2014

J Virol

123

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Dengue virus (DENV) interacts with host cellular factors to construct a more favorable environment for replication, and the interplay between DENV and the host cellular cytoskeleton may represent one of the potential antiviral targeting sites. However, the involvement of cellular vimentin intermediate filaments in DENV replication has been explored less. Here, we revealed the direct interaction between host cellular vimentin and DENV nonstructural protein 4A (NS4A), a known component of the viral replication complex (RC), during DENV infection using tandem affinity purification, coimmunoprecipitation, and scanning electron microscopy. Furthermore, the dynamics of vimentin-NS4A interaction were demonstrated by using confocal three-dimensional (3D) reconstruction and proximity ligation assay. Most importantly, we report for the first time the discovery of the specific region of NS4A that interacts with vimentin lies within the first 50 amino acid residues at the cytosolic N-terminal domain of NS4A (N50 region). Besides identifying vimentin-NS4A interaction, vimentin reorganization and phosphorylation by calcium calmodulin-dependent protein kinase II occurs during DENV infection, signifying that vimentin reorganization is important in maintaining and supporting the DENV RCs. Interestingly, we found that gene silencing of vimentin by small interfering RNA induced a significant alteration in the distribution of RCs in DENV-infected cells. This finding further supports the crucial role of intact vimentin scaffold in localizing and concentrating DENV RCs at the perinuclear site, thus facilitating efficient viral RNA replication. Collectively, our findings implicate the biological and functional significance of vimentin during DENV replication, as we propose that the association of DENV RCs with vimentin is mediated by DENV NS4A.

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Section: Discussionmentioning

confidence: 99%

Cellular Vimentin Regulates Construction of Dengue Virus Replication Complexes through Interaction with NS4A Protein

Teo

Chu

2014

J Virol

123

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“…5 After posttranslational proteolytic maturation of the polyprotein, the virus-encoded RNA-dependent RNA polymerase (NS5) produces negative-sense (2)RNA that acts as a template for feedback-amplified generation of (1)ssRNA that may be subsequently encapsidated for DENV progeny assembly in the Golgi apparatus. 6 Four DENV serotypes (DENV1-4) share nucleotide sequence homology, but each have unique immunoreactivity. Thus, consecutive infection by different serotypes provides an explanation for progression into clinical pathology, because subneutralizing cross-reactive antibodies may enhance DENV infection via Fc-receptor (FcR)-bearing cells.…”

Section: Introductionmentioning

confidence: 99%

Dengue virus binding and replication by platelets

Simon

Sutherland

Pryzdial

2015

Blood

143

161

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Key Points• Platelets replicate and produce infectious DENV.• DENV binds directly to platelets using DC-SIGN and heparan sulfate proteoglycan as primary receptors.Dengue virus (DENV) infection causes ∼200 million cases of severe flulike illness annually, escalating to life-threatening hemorrhagic fever or shock syndrome in ∼500 000. Although thrombocytopenia is typical of both mild and severe diseases, the mechanism triggering platelet reduction is incompletely understood. As a probable initiating event, direct purified DENV-platelet binding was followed in the current study by quantitative reverse transcription-polymerase chain reaction and confirmed antigenically. Approximately 800 viruses specifically bound per platelet at 37°C. Fewer sites were observed at 25°C, the blood bank storage temperature (∼350 sites), or 4°C, known to attenuate virus cell entry (∼200 sites). Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and heparan sulfate proteoglycan were implicated as coreceptors because only the combination of anti-DC-SIGN and lowmolecular-weight heparin prevented binding. Interestingly, at 37°C and 25°C, platelets replicated the positive sense single-stranded RNA genome of DENV by up to ∼4-fold over 7 days. Further time course experiments demonstrated production of viral NS1 protein, which is known to be highly antigenic in patient serum. The infectivity of DENV intrinsically decayed in vitro, which was moderated by plateletmediated generation of viable progeny. This was shown using a transcription inhibitor and confirmed by freeze-denatured platelets being incapable of replicating the DENV genome. For the first time, these data demonstrate that platelets directly bind DENV saturably and produce infectious virus. Thus, expression of antigen encoded by DENV is a novel consideration in the pathogen-induced thrombocytopenia mechanism. These results furthermore draw attention to the possibility that platelets may produce permissive RNA viruses in addition to DENV. (Blood. 2015;126(3):378-385)

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“…Pertenece a la familia Flaviviridae y es un virus envuelto con genoma ARN monocatenario de polaridad positiva [ssRNA(+)] que codifica para tres proteínas estructurales (C, prM, E) y siete no estructurales (NS1, NS2A, NS2B, NS3, NS4A, NS4B y NS5) (Figura 1), involucradas en la replicación del ARN, el ensamblaje del virus y la modulación de la respuesta inmune de la célula hospedera [7][8][9][10] (Tabla 1). Múltiples monómeros de la proteína C encapsidan el ARN viral para formar la nucleocápside 11,12 , la que está rodeada por una bicapa lipídica de origen celular donde se encuentran ancladas las proteínas M (matriz) y E (envoltura) 13 .…”

Section: Virus Dengue Y Ciclo De Replicaciónunclassified

“…Funciones Referencias NS1 -Indicador de replicación temprana en Flavivirus -Posiblemente participa en la replicación del ARN (7,8) NS2A -Inhibe la vía de señalización del interferón tipo 1 (IFN I) al reducir la activación de la proteína para la transducción de señal y activación de la transcripción (STAT) sabilizado del aumento paulatino de la permeabilidad vascular que conlleva a la pérdida de plasma y fluidos, ocasionando uno de los signos más importantes como es la hemoconcentración, además del desorden en la hemostasis, que resulta en cambios vasculares, trombocitopenia y coagulopatía. En pacientes con DF se han reportado concentraciones plasmáticas elevadas de IL-12, pero esta citoquina está totalmente ausente en pacientes con DHF.…”

Section: Proteína No Estructuralunclassified