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Molecular Research on Arboviruses Infection

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 17943

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Special Issue Editor

Dr. Byron Martina

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Guest Editor

Artemis One Health, Delft, The Netherlands
Interests: dengue virus infection

Special Issue Information

Dear Colleagues,

Emerging and existing arboviruses represent a constant threat in all regions of the world. Understanding the molecular mechanisms of pathogenesis and protective immunity is an important endeavour for designing new therapeutic interventions. The molecular pathogenesis of arbovirus infections describes our current understanding of the pathogenesis of selected arboviruses, such as dengue, Zika, West Nile, Rift Valley fever, chikungunya, and many others. Molecular pathogenesis may focus on, but is not restricted to, for instance tropism, host–pathogen interactions at a cellular and molecular level, study of virulence factors, mico-evolution, host resistance to pathogens, and factors driving the emergence of new viruses. Deciphering the specific aberrant cell signalling pathways in disease caused by arboviruses is an important piece in the molecular biology puzzle underlying these diseases. Understanding the ubiquitous pathways implicated in the disease, providing numerous potential therapeutic targets, may also be crucial for researchers in order to move forward. Consider, for instance, dengue, which consists of four serotypes. Although primary infection confers durable, if not life-long protection against re-infection by a homologous dengue virus serotype, secondary infection by a heterologous serotype is considered the most important risk factor for severe disease. However, the molecular mechanisms of, for instance, antibody-dependent enhancement, antibody glycosylation, original antigenic sin, mitochondrial dysfunction, pyroptosis, endothelium cell permeability, and so on, which have been associated with severe diseases remaining poorly understood. This Special Issue aims to bring this knowledge together and to identify the gaps in our understanding of the molecular mechanisms of evolution and pathogenesis.

Dr. Byron Martina
Guest Editor

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Keywords

Arboviruses Infection
Virulence Factors
Mico-Evolution
Molecular Pathogenesis
Cell Death
Aberrant Cell Signaling Pathways
Therapeutic Targets

Published Papers (5 papers)

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Research

15 pages, 2905 KiB

Open AccessArticle

CHOP Pro-Apoptotic Transcriptional Program in Response to ER Stress Is Hacked by Zika Virus

by Jonathan Turpin, Daed El-Safadi, Grégorie Lebeau, Etienne Frumence, Philippe Desprès, Wildriss Viranaïcken and Pascale Krejbich-Trotot

Int. J. Mol. Sci. 2021, 22(7), 3750; https://doi.org/10.3390/ijms22073750 - 3 Apr 2021

Cited by 17 | Viewed by 5190

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus considered as a threat to human health due to large epidemics and serious clinical outcomes such as microcephaly in new-borns. Like all flaviviruses, ZIKV relies on the cellular machinery to complete its viral cycle, with the endoplasmic reticulum (ER) being the critical site of viral replication factories. The sudden high protein load in the ER induces an ER stress to which the cell responds with an appropriate unfolded protein response (UPR) in an attempt to restore its disturbed homeostasis. When the restoration fails, the cell signalling leads to a programmed cell death by apoptosis with the upregulation of the UPR-induced C/EBP homologous protein (CHOP) which acts as the main trigger for this fatal outcome. Our previous studies have shown the ability of ZIKV to manipulate various cellular responses in order to optimize virus production. ZIKV is able to delay apoptosis to its benefit and although ER stress is induced, the UPR is not complete. Here we discovered that ZIKV impairs the expression of CHOP/DDIT3, the main factor responsible of ER-stress driven apoptosis. Surprisingly, the mechanism does not take place at the transcriptional level but at the translational level. Full article

(This article belongs to the Special Issue Molecular Research on Arboviruses Infection)

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19 pages, 3121 KiB

Open AccessArticle

Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1

by Zi-Yi Lu, Miao-Huei Cheng, Chia-Yi Yu, Yee-Shin Lin, Trai-Ming Yeh, Chia-Ling Chen, Chien-Chin Chen, Shu-Wen Wan and Chih-Peng Chang

Int. J. Mol. Sci. 2020, 21(24), 9702; https://doi.org/10.3390/ijms21249702 - 19 Dec 2020

Cited by 17 | Viewed by 2643

Abstract

Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design. Full article

(This article belongs to the Special Issue Molecular Research on Arboviruses Infection)

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14 pages, 3495 KiB

Open AccessArticle

Inhibition of Orbivirus Replication by Aurintricarboxylic Acid

by Celia Alonso, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Luis Jiménez-Cabello, Javier Ortego and Aitor Nogales

Int. J. Mol. Sci. 2020, 21(19), 7294; https://doi.org/10.3390/ijms21197294 - 2 Oct 2020

Cited by 10 | Viewed by 2897

Abstract

Bluetongue virus (BTV) and African horse sickness virus (AHSV) are vector-borne viruses belonging to the Orbivirus genus, which are transmitted between hosts primarily by biting midges of the genus Culicoides. With recent BTV and AHSV outbreaks causing epidemics and important economy losses, there is a pressing need for efficacious drugs to treat and control the spread of these infections. The polyanionic aromatic compound aurintricarboxylic acid (ATA) has been shown to have a broad-spectrum antiviral activity. Here, we evaluated ATA as a potential antiviral compound against Orbivirus infections in both mammalian and insect cells. Notably, ATA was able to prevent the replication of BTV and AHSV in both cell types in a time- and concentration-dependent manner. In addition, we evaluated the effect of ATA in vivo using a mouse model of infection. ATA did not protect mice against a lethal challenge with BTV or AHSV, most probably due to the in vivo effect of ATA on immune system regulation. Overall, these results demonstrate that ATA has inhibitory activity against Orbivirus replication in vitro, but further in vivo analysis will be required before considering it as a potential therapy for future clinical evaluation. Full article

(This article belongs to the Special Issue Molecular Research on Arboviruses Infection)

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13 pages, 2366 KiB

Open AccessArticle

Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo

by Fu-Kai Chuang, Ching-Len Liao, Ming-Kuan Hu, Yi-Lin Chiu, An-Rong Lee, Shih-Ming Huang, Yu-Lung Chiu, Pei-Ling Tsai, Bo-Cyuan Su, Tsung-Hsien Chang, Chang-Chi Lin, Chih-Chin Shih and Li-Chen Yen

Int. J. Mol. Sci. 2020, 21(11), 4050; https://doi.org/10.3390/ijms21114050 - 5 Jun 2020

Cited by 8 | Viewed by 3414

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne flaviviruses that cause severe illness after infection. Currently, there are no specific or effective treatments against DENV and ZIKV. Previous studies have shown that tyrosine kinase activities and signal transduction are involved in flavivirus replication, suggesting a potential therapeutic strategy for DENV and ZIKV. In this study, we found that compound L3 can significantly reduce viral protein expression and viral titers in HEK-293, MCF-7, HepG2, and Huh-7 cells and exhibits superior therapeutic efficacy against flaviviral infection compared to other tyrosine kinase inhibitors. In addition, compound L3 can decrease endogenous HER2 activation and inhibit the phosphorylation of the HER2 downstream signaling molecules Src and ERK1/2, the levels of which have been associated with viral protein expression in MCF-7 cells. Moreover, silencing HER2 diminished DENV-2 and ZIKV expression in MCF-7 cells, which suggests that HER2 activity is involved in flavivirus replication. Furthermore, in DENV-2-infected AG129 mice, treatment with compound L3 increased the survival rates and reduced the viremia levels. Overall, compound L3 demonstrates therapeutic efficacy both in vitro and in vivo and could be developed as a promising antiviral drug against emerging flaviviruses or for concurrent DENV and ZIKV outbreaks. Full article

(This article belongs to the Special Issue Molecular Research on Arboviruses Infection)

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14 pages, 1963 KiB

Open AccessArticle

Elevation of Cleaved p18 Bax Levels Associated with the Kinetics of Neuronal Cell Death during Japanese Encephalitis Virus Infection

by Prapimpun Wongchitrat, Arisara Samutpong, Hatairat Lerdsamran, Jarunee Prasertsopon, Montri Yasawong, Piyarat Govitrapong, Pilaipan Puthavathana and Kuntida Kitidee

Int. J. Mol. Sci. 2019, 20(20), 5016; https://doi.org/10.3390/ijms20205016 - 10 Oct 2019

Cited by 9 | Viewed by 2853

Abstract

Japanese encephalitis virus (JEV) infection induces uncontrolled neuronal apoptosis, leading to irreversible brain damage. However, the mechanism of JEV-induced neuronal apoptosis has not been clearly elucidated. This study aimed to investigate both virus replication and neuronal cell apoptosis during JEV infection in human neuroblastoma SH-SY5Y cells. As a result, the kinetic productions of new viral progeny were time- and dose-dependent. The stimulation of SH-SY5Y cell apoptosis was dependent on the multiplicity of infections (MOIs) and infection periods, particularly during the late period of infection. Interestingly, we observed that of full-length Bax (p21 Bax) level started to decrease, which corresponded to the increased level of its cleaved form (p18 Bax). The formation of p18 Bax resulting in cytochrome c release into the cytosol appeared to correlate with JEV-induced apoptotic cell death together with the activation of caspase-3/7 activity, especially during the late stage of a robust viral infection. Therefore, our results suggest another possible mechanism of JEV-induced apoptotic cell death via the induction of the proteolysis of endogenous p21 Bax to generate p18 Bax. This finding could be a new avenue to facilitate novel drug discovery for the further development of therapeutic treatments that could relieve neuronal damage from JEV infection. Full article

(This article belongs to the Special Issue Molecular Research on Arboviruses Infection)

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