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Molecular Research on Emerging Mosquito-Transmitted RNA Viruses

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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 2019) | Viewed by 46603

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Prof. Kristy Murray

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Department of Pediatrics, Section of Pediatric Tropical Medicine, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital One Baylor Plaza, BCM 320, Houston, TX, USA
Interests: vector-borne and zoonotic diseases; West Nile; dengue; chagas; rabies
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Philippe Desprès

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Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Université de La Réunion, INSERM UMR 1187, CNRS 9192, IRD 249. Technology platform CYROI, 2 rueMaxime Rivière, 97491 Sainte-Clotilde, La Réunion, France
Interests: molecular virology; mosquito-borne RNA virus; viral pathogenicity; viral disease; host-virus interactions; viral diagnosis; vaccine; antiviral compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mosquito-transmitted RNA viruses (arboviruses), such as dengue, Japanese encephalitis, West Nile, yellow fever, Zika, chikungunya, Ross River, and Rift Valley fever, are becoming major public health concerns due to their global dispersion. In the context of increasing numbers of outbreaks and severity of infection, it is urgent to understand the mechanisms underlying enhanced virulence of arboviruses in humans. Consequently, molecular research is important for improving our knowledge on viral and cellular factors that impact the pathogenicity of arboviruses in their mosquito vectors and mammalian hosts, including humans. In addition, the analysis of interdependent consequences of viral factors and host responses has the potential to reveal important pathways involved in the pathogenicity of arboviruses in humans. In this Special Issue, the contributors are warmly invited to publish their research works on molecular biology of arboviruses, molecular basis of their pathogenicity in link with the host–cell response to infection, and innate immune evasion strategies in arthropod vectors and mammalian hosts.

Sincerely,

Prof. Kristy Murray
Prof. Philippe Desprès
Guest Editors

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Keywords

arboviruses
dengue
Japanese encephalitis virus
yellow fever virus
West Nile virus
Zika virus
Chikungunya virus
Ross River virus
Rift Valley Fever virus
molecular virology
host-virus interactions
antiviral immunity
viral pathogenicity

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Molecular Research on Emerging Mosquito-Transmitted RNA Viruses 3.0 in International Journal of Molecular Sciences (1 article)

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Research

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18 pages, 2773 KiB

Open AccessArticle

TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy

by Li-Wei Chu, Chia-Jui Yang, Kuan-Jen Peng, Pei-Ling Chen, Shuu-Jiun Wang and Yueh-Hsin Ping

Int. J. Mol. Sci. 2019, 20(19), 4893; https://doi.org/10.3390/ijms20194893 - 2 Oct 2019

Cited by 20 | Viewed by 4156

Abstract

Dengue virus (DENV) infection triggers the activation of autophagy to facilitate the viral replication cycle from various aspects. Although a number of stimulators are proposed to activate autophagy, none of them appears prior to the uncoating process. Given that T-cell immunoglobulin and mucin domain 1 (TIM-1) receptor is a putative DENV receptor and promotes apoptotic body clearance by autophagy induction, it raises the possibility that TIM-1 may participate in the activation of DENV-induced autophagy. In this study, confocal images first revealed the co-localization of TIM-1 with autophagosomes in DENV-induced autophagy rather than rapamycin-induced autophagy, suggesting the co-transportation of TIM-1 with DENV during infection. The treatment of siRNA to knockdown TIM-1 expression in DENV-infected GFP-microtubule-associated protein light chain 3 (LC3)-Huh7.5 cells revealed that TIM-1 is required not only for DENV cellular internalization but also for autophagy activation. Furthermore, knockdown p85, a subunit of phosphoinositide 3-kinases (PI3Ks), which is co-localized with TIM-1 at rab5-positive endosomes caused the reduction of autophagy, indicating that TIM-1-mediated DENV-induced autophagy requires p85. Taken together, the current study uncovered TIM-1 as a novel factor for triggering autophagy in DENV infection through TIM-1-p85 axis, in addition to serving as a DENV receptor. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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20 pages, 12836 KiB

Open AccessArticle

Comparative Genomics, Infectivity and Cytopathogenicity of American Isolates of Zika Virus that Developed Persistent Infections in Human Embryonic Kidney (HEK293) Cells

by Hebing Liu, Hsiao-Mei Liao, Bingjie Li, Shien Tsai, Guo-Chiuan Hung and Shyh-Ching Lo

Int. J. Mol. Sci. 2019, 20(12), 3035; https://doi.org/10.3390/ijms20123035 - 21 Jun 2019

Cited by 11 | Viewed by 6812

Abstract

Zika virus (ZIKV) transmission can cause serious fetal neurological abnormalities. ZIKV persistence in various human cells and tissues can serve as infectious reservoirs and post serious threats to public health. The human embryonic kidney (HEK293) cell line with known neuronal developmental properties was readily infected by ZIKV in a strain-dependent fashion. Significant cytopathic effect in HEK293 cells infected by the prototype MR 766 strain of ZIKV resulted in complete loss of cells, while small numbers of HEK293 cells infected by contemporary ZIKV isolates (PRV or FLR strain) continued to survive and regrow to confluency in the culture around two months after initial infection. Most, if not all, of the cells in the two resulting persistently ZIKV-infected HEK293 cell lines tested positive for ZIKV antigen. Compared to HEK293 control cells, the persistently ZIKV-infected HEK293 cells had slower growth rates with some cells undergoing apoptosis in culture. The “persistent ZIKVs” produced constitutively by both PRV and FLR strains ZIKV-infected HEK293 cells had significantly attenuated cell infectivity and/or cytopathogenicity. Comparative genome sequence analyses between the persistent ZIKVs and the original inoculum ZIKVs showed no clonal selection with specific gene mutations in the prolonged process of establishing persistently PRV strain ZIKV-infected HEK293 cells; while selection of ZIKV subclones with mutations in the envelope, protein pr and multiple NS genes was evident in developing persistently FLR strain ZIKV-infected HEK293 cell line. Our study provides molecular insights into the complex interplays of ZIKV and human host cells in establishing ZIKV persistence. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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10 pages, 5046 KiB

Open AccessCommunication

A Viral Polymerase Inhibitor Reduces Zika Virus Replication in the Reproductive Organs of Male Mice

by Sofie Jacobs, Leen Delang, Eric Verbeken, Johan Neyts and Suzanne J.F. Kaptein

Int. J. Mol. Sci. 2019, 20(9), 2122; https://doi.org/10.3390/ijms20092122 - 29 Apr 2019

Cited by 12 | Viewed by 3738

Abstract

In humans, Zika virus and viral RNA have been detected in semen up to 2.2 months and 6 months post infection (pi), respectively. Although the contribution of sexual transmission to the spread of ZIKV is too low to sustain an outbreak, it can increase the risk of infection and the epidemic size as well as prolong the duration of an outbreak. In this study, we explored the potential of antivirals to serve as an effective strategy to prevent sexual transmission. Male AG129 mice infected with a ZIKV isolate from Suriname were treated with the nucleoside analog, 7-deaza-2′-C-methyladenosine (7DMA), that was previously shown to be efficacious in reducing ZIKV viremia and delaying ZIKV-induced disease in mice. Following treatment, viral RNA and infectious virus titers were consistently reduced in the male reproductive organs compared to vehicle-treated mice. This reduction of ZIKV loads in the testis was confirmed by the detection of lower levels of ZIKV antigens. Our data illustrate the value of this mouse model to validate the efficacy of new potential ZIKV drugs at the level of the male reproductive system. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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7 pages, 410 KiB

Open AccessCommunication

Phenotypic and Genotypic Characterization of West Nile Virus Isolate 2004Hou3

by Shannon E. Ronca, Rodion Gorchakov, Rebecca Berry, R. Elias Alvarado, Sarah M. Gunter and Kristy O. Murray

Int. J. Mol. Sci. 2019, 20(8), 1936; https://doi.org/10.3390/ijms20081936 - 19 Apr 2019

Cited by 2 | Viewed by 2546

Abstract

West Nile virus (WNV) is an arbovirus with important public health implications globally. This study characterizes a viral isolate, 2004Hou3, in comparison with the NY99 strain from the original WNV outbreak in New York, USA. NextGen sequencing was used to compare the viral isolates genetically, while wild-type C57/BL6 mice were used to compare pathogenicity and viral persistence. Significant differences in survival and clinical presentations were noted, with minor genetic variations between the two strains potentially offering an explanation. One notable difference is that 5 of 35 mice infected with the 2004Hou3 strain developed hind limb flaccid paralysis, suggesting its possible use as a small animal pathogenesis model for this clinical characteristic often observed in human WN neuroinvasive disease patients but not reported in other animal models of infection. Overall, this study suggests that 2004Hou3 is a less pathogenic strain with potential for use in long-term outcome studies using small animal models. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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11 pages, 888 KiB

Open AccessArticle

Optimizing PCR Detection of West Nile Virus from Body Fluid Specimens to Delineate Natural History in an Infected Human Cohort

by Rodion Gorchakov, Bonnie E. Gulas-Wroblewski, Shannon E. Ronca, Jeanne C. Ruff, Melissa S. Nolan, Rebecca Berry, R. Elias Alvarado, Sarah M. Gunter and Kristy O. Murray

Int. J. Mol. Sci. 2019, 20(8), 1934; https://doi.org/10.3390/ijms20081934 - 19 Apr 2019

Cited by 20 | Viewed by 4024

Abstract

West Nile virus (WNV), a mosquito-borne arbovirus, remains a major global health concern. In this study, we optimized PCR methods then assessed serially-collected whole blood (WB), urine (UR), saliva, and semen specimens from a large cohort of WNV-positive participants to evaluate the natural history of infection and persistent shedding of WNV RNA. Viral RNA extraction protocols for frozen WB and UR specimens were optimized and validated through spiking experiments to maximize recovery of viral RNA from archived specimens and to assess the degradation of WNV RNA in stored UR specimens. The resultant procedures were used in conjunction with PCR detection to identify WNV-positive specimens and to quantify their viral loads. A total of 59 of 352 WB, 10 of 38 UR, and 2 of 34 saliva specimens tested positive for WNV RNA. Although a single semen specimen was positive 22 days post onset, we could not definitively confirm the presence of WNV RNA in the remaining specimens. WNV RNA-positive UR specimens exhibited profound loss of viral RNA during storage, highlighting the need for optimal preservation pre-storage. This study provides optimized methods for WNV RNA detection among different fluid types and offers alternative options for diagnostic testing during the acute stages of WNV. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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18 pages, 3554 KiB

Open AccessArticle

SAMHD1 Enhances Chikungunya and Zika Virus Replication in Human Skin Fibroblasts

by Sineewanlaya Wichit, Rodolphe Hamel, Andreas Zanzoni, Fodé Diop, Alexandra Cribier, Loïc Talignani, Abibatou Diack, Pauline Ferraris, Florian Liegeois, Serge Urbach, Peeraya Ekchariyawat, Andres Merits, Hans Yssel, Monsef Benkirane and Dorothée Missé

Int. J. Mol. Sci. 2019, 20(7), 1695; https://doi.org/10.3390/ijms20071695 - 5 Apr 2019

Cited by 21 | Viewed by 5217

Abstract

Chikungunya virus (CHIKV) and Zika virus (ZIKV) are emerging arboviruses that pose a worldwide threat to human health. Currently, neither vaccine nor antiviral treatment to control their infections is available. As the skin is a major viral entry site for arboviruses in the human host, we determined the global proteomic profile of CHIKV and ZIKV infections in human skin fibroblasts using Stable Isotope Labelling by Amino acids in Cell culture (SILAC)-based mass-spectrometry analysis. We show that the expression of the interferon-stimulated proteins MX1, IFIT1, IFIT3 and ISG15, as well as expression of defense response proteins DDX58, STAT1, OAS3, EIF2AK2 and SAMHD1 was significantly up-regulated in these cells upon infection with either virus. Exogenous expression of IFITs proteins markedly inhibited CHIKV and ZIKV replication which, accordingly, was restored following the abrogation of IFIT1 or IFIT3. Overexpression of SAMHD1 in cutaneous cells, or pretreatment of cells with the virus-like particles containing SAMHD1 restriction factor Vpx, resulted in a strong increase or inhibition, respectively, of both CHIKV and ZIKV replication. Moreover, silencing of SAMHD1 by specific SAMHD1-siRNA resulted in a marked decrease of viral RNA levels. Together, these results suggest that IFITs are involved in the restriction of replication of CHIKV and ZIKV and provide, as yet unreported, evidence for a proviral role of SAMHD1 in arbovirus infection of human skin cells. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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11 pages, 3098 KiB

Open AccessArticle

A Viperin Mutant Bearing the K358R Substitution Lost its Anti-ZIKA Virus Activity

by Bénédicte Vanwalscappel, Gilles Gadea and Philippe Desprès

Int. J. Mol. Sci. 2019, 20(7), 1574; https://doi.org/10.3390/ijms20071574 - 29 Mar 2019

Cited by 10 | Viewed by 3773

Abstract

Interferon-induced viperin (VP) was identified as playing an important role in the innate immune response against Zika virus (ZIKV). The 361 amino acid long human VP protein comprises of a highly conserved C-terminal region, which has been associated with VP antiviral properties against ZIKV. In the present study, we sought to determine whether the very last C-terminal amino-acid residues of VP might play a role in VP-mediated ZIKV inhibition. To address this issue, a recombinant human viperin (rVP^wt) was overexpressed by transfection in human epithelial A549 cells. We confirmed that transient overexpression of rVP^wt prior to ZIKV infection dramatically reduced viral replication in A549 cells. Deletion of the last 17 C-terminal amino acids of VP resulted in a higher expression level of mutant protein compared to wild-type VP. Mutational analysis revealed that residue substitution at positions 356 to 360 with five alanine led to the same phenotype. The charged residues Asp356, Lys358, and Asp360 were then identified to play a role in the weak level of VP^wt protein in A549 cells. Mutant VP bearing the D360A substitution partially rescued ZIKV growth in A549 cells. Remarkably, a single Lys-to-Arg substitution at position 358 was sufficient to abrogate VP antiviral activity against ZIKV. In conclusion, our study showed that Asp356, Lys358, and Asp360 may have an influence on biochemical properties of VP. Our major finding was that Lys358 was a key amino-acid in VP antiviral properties against ZIKV. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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16 pages, 6605 KiB

Open AccessArticle

Clinical Importance of Placental Testing among Suspected Cases of Congenital Zika Syndrome

by Maxim D. Seferovic, Michelle Turley, Gregory C. Valentine, Martha Rac, Eumenia C. C. Castro, Angela M. Major, Brianna Sanchez, Catherine Eppes, Magdalena Sanz-Cortes, James Dunn, Tiffany F. Kautz, James Versalovic, Kenneth L. Muldrew, Timothy Stout, Michael A. Belfort, Gail Demmler-Harrison and Kjersti M. Aagaard

Int. J. Mol. Sci. 2019, 20(3), 712; https://doi.org/10.3390/ijms20030712 - 7 Feb 2019

Cited by 9 | Viewed by 4127

Abstract

Contemporaneous Zika virus (ZIKV) strains can cause congenital Zika syndrome (CZS). Current ZIKV clinical laboratory testing strategies are limited and include IgM serology (which may wane 12 weeks after initial exposure) and nucleic acid testing (NAT) of maternal serum, urine, and placenta for (+) strand ZIKV RNA (which is often transient). The objectives of this study were to determine if use of additional molecular tools, such as quantitative PCR and microscopy, would add to the diagnostic value of current standard placental ZIKV testing in cases with maternal endemic exposure and indeterminate testing. ZIKV RNA was quantified from dissected sections of placental villi, chorioamnion sections, and full cross-sections of umbilical cord in all cases examined. Quantitation with high-resolution automated electrophoresis determined relative amounts of precisely verified ZIKV (74-nt amplicons). In order to localize and visualize stable and actively replicating placental ZIKV in situ, labeling of flaviviridae glycoprotein, RNA ISH against both (+) and (−) ZIKV-specific ssRNA strands, and independent histologic examination for significant pathologic changes were employed. We demonstrate that the use of these molecular tools added to the diagnostic value of placental ZIKV testing among suspected cases of congenital Zika syndrome with poorly ascribed maternal endemic exposure. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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19 pages, 1219 KiB

Open AccessArticle

Transcriptional Profile of Aedes aegypti Leucine-Rich Repeat Proteins in Response to Zika and Chikungunya Viruses

by Liming Zhao, Barry W. Alto and Dongyoung Shin

Int. J. Mol. Sci. 2019, 20(3), 615; https://doi.org/10.3390/ijms20030615 - 31 Jan 2019

Cited by 11 | Viewed by 4453

Abstract

Aedes aegypti (L.) is the primary vector of chikungunya, dengue, yellow fever, and Zika viruses. The leucine-rich repeats (LRR)-containing domain is evolutionarily conserved in many proteins associated with innate immunity in invertebrates and vertebrates, as well as plants. We focused on the AaeLRIM1 and AaeAPL1 gene expressions in response to Zika virus (ZIKV) and chikungunya virus (CHIKV) infection using a time course study, as well as the developmental expressions in the eggs, larvae, pupae, and adults. RNA-seq analysis data provided 60 leucine-rich repeat related transcriptions in Ae. aegypti in response to Zika virus (Accession number: GSE118858, accessed on: August 22, 2018, GEO DataSets). RNA-seq analysis data showed that AaeLRIM1 (AAEL012086-RA) and AaeAPL1 (AAEL009520-RA) were significantly upregulated 2.5 and 3-fold during infection by ZIKV 7-days post infection (dpi) of an Ae. aegypti Key West strain compared to an Orlando strain. The qPCR data showed that LRR-containing proteins related genes, AaeLRIM1 and AaeAPL1, and five paralogues were expressed 100-fold lower than other nuclear genes, such as defensin, during all developmental stages examined. Together, these data provide insights into the transcription profiles of LRR proteins of Ae. aegypti during its development and in response to infection with emergent arboviruses. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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Review

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16 pages, 934 KiB

Open AccessReview

Advances in Zika Virus–Host Cell Interaction: Current Knowledge and Future Perspectives

by Jae Kyung Lee and Ok Sarah Shin

Int. J. Mol. Sci. 2019, 20(5), 1101; https://doi.org/10.3390/ijms20051101 - 4 Mar 2019

Cited by 38 | Viewed by 6635

Abstract

Emerging mosquito-transmitted RNA viruses, such as Zika virus (ZIKV) and Chikungunya represent human pathogens of an immense global health problem. In particular, ZIKV has emerged explosively since 2007 to cause a series of epidemics in the South Pacific and most recently in the Americas. Although typical ZIKV infections are asymptomatic, ZIKV infection during pregnancy is increasingly associated with microcephaly and other fetal developmental abnormalities. In the last few years, genomic and molecular investigations have established a remarkable progress on the pathogenic mechanisms of ZIKV infection using in vitro and in vivo models. Here, we highlight recent advances in ZIKV-host cell interaction studies, including cellular targets of ZIKV, ZIKV-mediated cell death mechanisms, host cell restriction factors that limit ZIKV replication, and immune evasion mechanisms utilized by ZIKV. Understanding of the mechanisms of ZIKV–host interaction at the cellular level will contribute crucial insights into the development of ZIKV therapeutics and vaccines. Full article

(This article belongs to the Special Issue Molecular Research on Emerging Mosquito-Transmitted RNA Viruses)

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