Special Issue "Flavivirus Replication and Pathogenesis"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editor

Dr. Young-Min Lee
E-Mail Website
Guest Editor
Department of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA
Interests: Japanese encephalitis virus; flavivirus; porcine reproductive and respiratory syndrome virus; arterivirus; replication; virus–host interactions; pathogenesis; vaccine

Special Issue Information

Dear colleague,

Within the family Flaviviridae, the genus Flavivirus consists of more than 50 species; in any part of the globe where humans can live, at least one flavivirus species can be found. Pathogenic flaviviruses are primarily transmitted by blood-sucking mosquitoes or ticks. These species include a significant number of emerging and re-emerging arboviruses of global significance, such as Japanese encephalitis, West Nile, Zika, dengue, yellow fever, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever viruses. Infections by these pathogens can cause a wide spectrum of severe neurological and non-neurological diseases in humans and/or animals. Although the structure of these viruses and their gene products are relatively well defined thus far, they still pose a significant threat to humans and/or animals, and in most cases, no specific medical interventions are available. This Special Issue seeks all types of manuscripts (e.g., reviews, research articles, and short communications) that will highlight and advance our current understanding of these viruses, specifically the molecular aspects of their replication and pathogenesis, and prospectively discuss new challenges and unresolved issues. We expect this publication opportunity will yield new insights that will contribute directly to the development of new control strategies to prevent or treat infections caused by these clinically important pathogens.

Dr. Young-Min Lee
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • flavivirus 
  • viral replication 
  • viral pathogenesis 
  • virus-host interactions 
  • host immune responses

Published Papers (6 papers)

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Research

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Open AccessArticle
A Dengue Virus Type 2 (DENV-2) NS4B-Interacting Host Factor, SERP1, Reduces DENV-2 Production by Suppressing Viral RNA Replication
Viruses 2019, 11(9), 787; https://doi.org/10.3390/v11090787 - 27 Aug 2019
Abstract
Host cells infected with dengue virus (DENV) often trigger endoplasmic reticulum (ER) stress, a key process that allows viral reproduction, without killing the host cells until the late stage of the virus life-cycle. However, little is known regarding which DENV viral proteins interact [...] Read more.
Host cells infected with dengue virus (DENV) often trigger endoplasmic reticulum (ER) stress, a key process that allows viral reproduction, without killing the host cells until the late stage of the virus life-cycle. However, little is known regarding which DENV viral proteins interact with the ER machinery to support viral replication. In this study, we identified and characterized a novel host factor, stress-associated ER protein 1 (SERP1), which interacts with the DENV type 2 (DENV-2) NS4B protein by several assays, for example, yeast two-hybrid, subcellular localization, NanoBiT complementation, and co-immunoprecipitation. A drastic increase (34.5-fold) in the SERP1 gene expression was observed in the DENV-2-infected or replicon-transfected Huh7.5 cells. The SERP1 overexpression inhibited viral yields (37-fold) in the DENV-2-infected Huh7.5 cells. In contrast, shRNAi-knockdown and the knockout of SERP1 increased the viral yields (3.4- and 16-fold, respectively) in DENV-2-infected HEK-293 and Huh7.5 cells, respectively. DENV-2 viral RNA replication was severely reduced in stable SERP1-expressing Huh7.5 cells transfected with DENV-2 replicon plasmids. The overexpression of DENV-2 NS4B alleviated the inhibitory effect of SERP1 on DENV-2 RNA replication. Taking these results together, we hypothesized that SERP1 may serve as an antiviral player during ER stress to restrict DENV-2 infection. Our studies revealed novel anti-DENV drug targets that may facilitate anti-DENV drug discovery. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Open AccessArticle
Screening of Duck Tembusu Virus NS3 Interacting Host Proteins and Identification of Its Specific Interplay Domains
Viruses 2019, 11(8), 740; https://doi.org/10.3390/v11080740 - 12 Aug 2019
Abstract
NS3 protein is a member of the non-structural protein of duck Tembusu virus (DTMUV), which contains three domains, each of which has serine protease, nucleotide triphosphatase, and RNA helicase activities, respectively. It performs a variety of biological functions that are involved in the [...] Read more.
NS3 protein is a member of the non-structural protein of duck Tembusu virus (DTMUV), which contains three domains, each of which has serine protease, nucleotide triphosphatase, and RNA helicase activities, respectively. It performs a variety of biological functions that are involved in the regulation of the viral life cycle and host immune response. Based on the yeast two-hybrid system, we successfully transformed pGBKT7-NS3 bait plasmid into Y2H Gold, tested it to prove that it has no self-activation and toxicity, and then hybridized it with the prey yeast strain of the duck embryo fibroblast cDNA library for screening. After high-stringency selection, positive alignment with the National Center for Biotechnology Information database revealed nine potential interactive proteins: MGST1, ERCC4, WIF1, WDR75, ACBD3, PRDX1, RPS7, ND5, and LDHA. The most interesting one (PRDX1) was selected to be verified with full-length NS3 protein and its three domains S7/DEXDc/HELICc using yeast regressive verification and GST Pull-Down assay. It denoted that PRDX1 does indeed interact with HELICc domains of NS3. NS3 is involved in the RNA uncoiling process of viral replication, which may cause mitochondrial overload to create oxidative stress (OS) during DTMUV attack. We deduced that the HELICc domain binding partner PRDX1, which regulates the p38/mitogen-activated protein kinase pathway (p38/MAPK) to avert OS, causing apoptosis, making it possible for viruses to escape host immune responses. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Open AccessArticle
Cellular Interleukin Enhancer-Binding Factor 2, ILF2, Inhibits Japanese Encephalitis Virus Replication In Vitro
Viruses 2019, 11(6), 559; https://doi.org/10.3390/v11060559 - 17 Jun 2019
Abstract
Japanese encephalitis virus (JEV) is a zoonotic mosquito-borne flavivirus which is the leading causative agent of viral encephalitis in endemic regions. JEV NS3 is a component of the viral replicase complex and is a multifunctional protein. In this study, interleukin enhancer-binding factor 2 [...] Read more.
Japanese encephalitis virus (JEV) is a zoonotic mosquito-borne flavivirus which is the leading causative agent of viral encephalitis in endemic regions. JEV NS3 is a component of the viral replicase complex and is a multifunctional protein. In this study, interleukin enhancer-binding factor 2 (ILF2) is identified as a novel cellular protein interacting with NS3 through co-immunoprecipitation assay and LC-MS/MS. The expression of ILF2 is decreased in JEV-infected human embryonic kidney (293T) cells. The knockdown of endogenous ILF2 by special short hairpin RNA (shRNA) positively regulates JEV propagation, whereas the overexpression of ILF2 results in a significantly reduced JEV genome synthesis. Further analysis revealed that the knockdown of ILF2 positively regulates viral replication by JEV replicon system studies. These results suggest that ILF2 may act as a potential antiviral agent against JEV infection. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Review

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Open AccessReview
Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus
Viruses 2019, 11(10), 960; https://doi.org/10.3390/v11100960 - 17 Oct 2019
Abstract
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, [...] Read more.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Open AccessReview
Flavivirus RNA-Dependent RNA Polymerase Interacts with Genome UTRs and Viral Proteins to Facilitate Flavivirus RNA Replication
Viruses 2019, 11(10), 929; https://doi.org/10.3390/v11100929 - 10 Oct 2019
Abstract
Flaviviruses, most of which are emerging and re-emerging human pathogens and significant public health concerns worldwide, are positive-sense RNA viruses. Flavivirus replication occurs on the ER and is regulated by many mechanisms and factors. NS5, which consists of a C-terminal RdRp domain [...] Read more.
Flaviviruses, most of which are emerging and re-emerging human pathogens and significant public health concerns worldwide, are positive-sense RNA viruses. Flavivirus replication occurs on the ER and is regulated by many mechanisms and factors. NS5, which consists of a C-terminal RdRp domain and an N-terminal methyltransferase domain, plays a pivotal role in genome replication and capping. The C-terminal RdRp domain acts as the polymerase for RNA synthesis and cooperates with diverse viral proteins to facilitate productive RNA proliferation within the replication complex. Here, we provide an overview of the current knowledge of the functions and characteristics of the RdRp, including the subcellular localization of NS5, as well as the network of interactions formed between the RdRp and genome UTRs, NS3, and the methyltransferase domain. We posit that a detailed understanding of RdRp functions may provide a target for antiviral drug discovery and therapeutics. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Open AccessReview
Exploring the Reservoir Hosts of Tick-Borne Encephalitis Virus
Viruses 2019, 11(7), 669; https://doi.org/10.3390/v11070669 - 22 Jul 2019
Abstract
Tick-borne encephalitis virus (TBEV) is an important arbovirus, which is found across large parts of Eurasia and is considered to be a major health risk for humans. Like any other arbovirus, TBEV relies on complex interactions between vectors, reservoir hosts, and the environment [...] Read more.
Tick-borne encephalitis virus (TBEV) is an important arbovirus, which is found across large parts of Eurasia and is considered to be a major health risk for humans. Like any other arbovirus, TBEV relies on complex interactions between vectors, reservoir hosts, and the environment for successful virus circulation. Hard ticks are the vectors for TBEV, transmitting the virus to a variety of animals. The importance of these animals in the lifecycle of TBEV is still up for debate. Large woodland animals seem to have a positive influence on virus circulation by providing a food source for adult ticks; birds are suspected to play a role in virus distribution. Bank voles and yellow-necked mice are often referred to as classical virus reservoirs, but this statement lacks strong evidence supporting their highlighted role. Other small mammals (e.g., insectivores) may also play a crucial role in virus transmission, not to mention the absence of any suspected reservoir host for non-European endemic regions. Theories highlighting the importance of the co-feeding transmission route go as far as naming ticks themselves as the true reservoir for TBEV, and mammalian hosts as a mere bridge for transmission. A deeper insight into the virus reservoir could lead to a better understanding of the development of endemic regions. The spatial distribution of TBEV is constricted to certain areas, forming natural foci that can be restricted to sizes of merely 500 square meters. The limiting factors for their occurrence are largely unknown, but a possible influence of reservoir hosts on the distribution pattern of TBE is discussed. This review aims to give an overview of the multiple factors influencing the TBEV transmission cycle, focusing on the role of virus reservoirs, and highlights the questions that are waiting to be further explored. Full article
(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

A Dengue Virus NS4B-interacting Host Factor, SERP1, Reduces Dengue Virus Production by Suppressing Viral RNA Replication
Authors: Jia-Ni Tian, Chi-Chen Yang, Chiu-Kai Chuang, Ming-Han Tsai, Ren-Huang Wu, Chiung-Tong Chen, Andrew Yueh

Title: Exploring the reservoir hosts of tick-borne encephalitis virus
Authors: Anna Michelitsch, Kerstin Wernike, Christine Klaus, Gerhard Dobler, Martin Beer

Screening of DTMUV NS3 interacted host cell proteins and identification of it’s specific interplay domains
Authors: Yawen Wang, Guanliu Yu, Jing Yang, Dalin He, He Liu, Yi Tang, Youxiang Diao

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