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24 pages, 3883 KiB

Open AccessArticle

Development, Characterization, and Application of Two Reporter-Expressing Recombinant Zika Viruses

by Sang-Im Yun, Byung-Hak Song, Michael E. Woolley, Jordan C. Frank, Justin G. Julander and Young-Min Lee

Viruses 2020, 12(5), 572; https://doi.org/10.3390/v12050572 - 22 May 2020

Cited by 8 | Viewed by 3353

Abstract

Zika virus (ZIKV), a mosquito-borne transplacentally transmissible flavivirus, is an enveloped virus with an ~10.8 kb plus-strand RNA genome that can cause neurological disease. To facilitate the identification of potential antivirals, we developed two reporter-expressing ZIKVs, each capable of expressing an enhanced green [...] Read more.

Zika virus (ZIKV), a mosquito-borne transplacentally transmissible flavivirus, is an enveloped virus with an ~10.8 kb plus-strand RNA genome that can cause neurological disease. To facilitate the identification of potential antivirals, we developed two reporter-expressing ZIKVs, each capable of expressing an enhanced green fluorescent protein or an improved luminescent NanoLuc luciferase. First, a full-length functional ZIKV cDNA clone was engineered as a bacterial artificial chromosome, with each reporter gene under the cap-independent translational control of a cardiovirus-derived internal ribosome entry site inserted downstream of the single open reading frame of the viral genome. Two reporter-expressing ZIKVs were then generated by transfection of ZIKV-susceptible BHK-21 cells with infectious RNAs derived by in vitro run-off transcription from the respective cDNAs. As compared to the parental virus, the two reporter-expressing ZIKVs grew to lower titers with slower growth kinetics and formed smaller foci; however, they displayed a genome-wide viral protein expression profile identical to that of the parental virus, except for two previously unrecognized larger forms of the C and NS1 proteins. We then used the NanoLuc-expressing ZIKV to assess the in vitro antiviral activity of three inhibitors (T-705, NITD-008, and ribavirin). Altogether, our reporter-expressing ZIKVs represent an excellent molecular tool for the discovery of novel antivirals. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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15 pages, 1473 KiB

Open AccessArticle

PERK-Mediated Unfolded Protein Response Signaling Restricts Replication of the Tick-Borne Flavivirus Langat Virus

by Tyler G. Lewy, Danielle K. Offerdahl, Jeffrey M. Grabowski, Eliza Kellman, Luwanika Mlera, Abhilash Chiramel and Marshall E. Bloom

Viruses 2020, 12(3), 328; https://doi.org/10.3390/v12030328 - 18 Mar 2020

Cited by 12 | Viewed by 3304

Abstract

The unfolded protein response (UPR) maintains protein-folding homeostasis in the endoplasmic reticulum (ER) and has been implicated as both beneficial and detrimental to flavivirus infection. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a sensor of the UPR, is commonly associated with antiviral [...] Read more.

The unfolded protein response (UPR) maintains protein-folding homeostasis in the endoplasmic reticulum (ER) and has been implicated as both beneficial and detrimental to flavivirus infection. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a sensor of the UPR, is commonly associated with antiviral effects during mosquito-borne flavivirus (MBFV) infection, but its relation to tick-borne flavivirus (TBFV) infection remains largely unexplored. In this study, we identified changes in UPR and autophagic activity during Langat virus (LGTV) infection. LGTV robustly activated UPR and altered autophagic flux. Knockdown of endogenous PERK in human cells resulted in increased LGTV replication, but not that of closely related Powassan virus (POWV). Finally, on examining changes in protein levels of components associated with UPR and autophagy in the absence of PERK, we could show that LGTV-infected cells induced UPR but did not lead to expression of C/EBP homologous protein (CHOP), an important downstream transcription factor of multiple stress pathways. From these data, we hypothesize that LGTV can antagonize other kinases that target eukaryotic initiation factor 2α (eIF2α), but not PERK, implicating PERK as a potential mediator of intrinsic immunity. This effect was not apparent for POWV, a more pathogenic TBFV, suggesting it may be better equipped to mitigate the antiviral effects of PERK. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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19 pages, 3128 KiB

Open AccessArticle

Assessment of Prolonged Dengue Virus Infection in Dermal Fibroblasts and Hair-Follicle Dermal Papilla Cells

by Kai-Che Wei, Wan-Ju Wei, Yi-Shan Liu, Li-Chen Yen and Tsung-Hsien Chang

Viruses 2020, 12(3), 267; https://doi.org/10.3390/v12030267 - 28 Feb 2020

Cited by 1 | Viewed by 3346

Abstract

Dengue virus (DENV)-mediated hair loss is one of the post-dengue fatigue syndromes and its pathophysiology remains unknown. Whether long-term or persistent infection with DENV in the scalp results in hair loss is unclear. In this study, we cultured human dermal fibroblasts (WS1 cells) [...] Read more.

Dengue virus (DENV)-mediated hair loss is one of the post-dengue fatigue syndromes and its pathophysiology remains unknown. Whether long-term or persistent infection with DENV in the scalp results in hair loss is unclear. In this study, we cultured human dermal fibroblasts (WS1 cells) and primary human hair-follicle dermal papilla cells (HFDPCs) in the long term with DENV-2 infection. The production of virion, the expression of inflammatory and anti-virus genes, and their signaling transduction activity in the infected cells were analyzed. DENV-2 NS3 protein and DENV-2 5′ UTR RNA were detected in fibroblasts and HFDPCs that were subjected to long-term infection with DENV-2 for 33 days. A significant amount of DENV-2 virion was produced by both WS1 cells and HFDPCs in the first two days of acute infection. The virion was also detected in WS1 cells that were infected in the long term, but HFDPCs failed to produce DENV-2 after long-term culture. Type I and type III interferons, and inflammatory cytokines were highly expressed in the acute phase of DENV infection in HFPDC and WS1 cells. However, in the long-term cultured cells, modest levels of anti-viral protein genes were expressed and we observed reduced signaling activity, which was correlated with the level of virus production changes. Long-term infection of DENV-2 downregulated the expression of hair growth regulatory factors, such as Rip1, Wnt1, and Wnt4. This in vitro study shows that the long-term infection with DENV-2 in dermal fibroblasts and dermal papilla cells may be involved with the prolonged-DENV-infection-mediated hair loss of post-dengue fatigue syndrome. However, direct evidence for viral replication in the human hair of a dengue victim or animal infection model is required. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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9 pages, 491 KiB

Open AccessArticle

Presence of Flavivirus Antibodies Does Not Lead to a Greater Number of Symptoms in a Small Cohort of Canadian Travelers Infected with Zika Virus

by Robert A. Kozak, Lee W. Goneau, Cedric DeLima, Olivia Varsaneux, AliReza Eshaghi, Erik Kristjanson, Romy Olsha, David Safronetz, Stephen Perusini, Christine Frantz and Jonathan B. Gubbay

Viruses 2020, 12(2), 140; https://doi.org/10.3390/v12020140 - 24 Jan 2020

Cited by 2 | Viewed by 1920

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving [...] Read more.

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure (n = 16) to those without any previous exposure (n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p-value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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22 pages, 13651 KiB

Open AccessArticle

An RNA Thermometer Activity of the West Nile Virus Genomic 3′-Terminal Stem-Loop Element Modulates Viral Replication Efficiency during Host Switching

by Alexandra Meyer, Marie Freier, Tobias Schmidt, Katja Rostowski, Juliane Zwoch, Hauke Lilie, Sven-Erik Behrens and Susann Friedrich

Viruses 2020, 12(1), 104; https://doi.org/10.3390/v12010104 - 15 Jan 2020

Cited by 15 | Viewed by 3779

Abstract

The 3′-terminal stem-loop (3′SL) of the RNA genome of the flavivirus West Nile (WNV) harbors, in its stem, one of the sequence elements that are required for genome cyclization. As cyclization is a prerequisite for the initiation of viral replication, the 3′SL was [...] Read more.

The 3′-terminal stem-loop (3′SL) of the RNA genome of the flavivirus West Nile (WNV) harbors, in its stem, one of the sequence elements that are required for genome cyclization. As cyclization is a prerequisite for the initiation of viral replication, the 3′SL was proposed to act as a replication silencer. The lower part of the 3′SL is metastable and confers a structural flexibility that may regulate the switch from the linear to the circular conformation of the viral RNA. In the human system, we previously demonstrated that a cellular RNA-binding protein, AUF1 p45, destabilizes the 3′SL, exposes the cyclization sequence, and thus promotes flaviviral genome cyclization and RNA replication. By investigating mutant RNAs with increased 3′SL stabilities, we showed the specific conformation of the metastable element to be a critical determinant of the helix-destabilizing RNA chaperone activity of AUF1 p45 and of the precision and efficiency of the AUF1 p45-supported initiation of RNA replication. Studies of stability-increasing mutant WNV replicons in human and mosquito cells revealed that the cultivation temperature considerably affected the replication efficiencies of the viral RNA variants and demonstrated the silencing effect of the 3′SL to be temperature dependent. Furthermore, we identified and characterized mosquito proteins displaying similar activities as AUF1 p45. However, as the RNA remodeling activities of the mosquito proteins were found to be considerably lower than those of the human protein, a potential cell protein-mediated destabilization of the 3′SL was suggested to be less efficient in mosquito cells. In summary, our data support a model in which the 3′SL acts as an RNA thermometer that modulates flavivirus replication during host switching. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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20 pages, 6233 KiB

Open AccessArticle

DEF Cell-Derived Exosomal miR-148a-5p Promotes DTMUV Replication by Negative Regulating TLR3 Expression

by Hongyan Guo, Anchun Cheng, Xingcui Zhang, YuHong Pan, Mingshu Wang, Juan Huang, Dekang Zhu, Shun Chen, Mafeng Liu, Xinxin Zhao, Ying Wu, Qiao Yang, Shaqiu Zhang, Yanling Yu, Leichang Pan, Bin Tian, Mujeeb Ur Rehman, Xiaoyue Chen, Yunya Liu, Ling Zhang, Zhongqiong Yin, Bo Jing and Renyong Jia Show full author list Hide full author list

Viruses 2020, 12(1), 94; https://doi.org/10.3390/v12010094 - 14 Jan 2020

Cited by 12 | Viewed by 3601

Abstract

Duck tembusu virus (DTMUV) is a single-stranded, positive-polarity RNA flavivirus that has caused considerable economic losses in China in recent years. Innate immunity represents the first line of defense against invading pathogens and serves as an important role in resisting viral infections. In [...] Read more.

Duck tembusu virus (DTMUV) is a single-stranded, positive-polarity RNA flavivirus that has caused considerable economic losses in China in recent years. Innate immunity represents the first line of defense against invading pathogens and serves as an important role in resisting viral infections. In this study, we found that the infection of ducks by DTMUV triggers Toll-like receptors (TLRs) and (RIG-I)-like receptors (RLRs) signaling pathways and inducing abundant of pro-inflammatory factors and type I interferons (IFNs), in which melanoma differentiation-associated gene 5 (MDA5) and Toll-like receptor 3 (TLR3) play important immunity roles, they can inhibit the replication process of DTMUV via inducing type I IFNs. Moreover, we demonstrated that type I IFNs can inhibit the DTMUV replication process in a time- and dose-dependent manner. Exosomes are small membrane vesicles that have important roles in intercellular communication. MicroRNAs (miRNAs) are small non-coding RNAs that can modulate gene expression and are common substances in exosomes. In our experiment, we successfully isolated DEF cells derived exosome for the first time and explored its function. Firstly, we found the expression of miR-148a-5p is significantly decreased following DTMUV infect. Then we found miR-148a-5p can target TLR3 and down-regulate the expression of TLR3, serving as a negative factor in innate immunity. Unfortunately, we cannot find miRNAs with different expression changes that can target MDA5. Lastly, our experimental results showed that TLR3 was one of the causes of miR-148a-5p reduction, suggesting that the high level of TLR3 after DTMUV infect can both trigger innate immunity and suppress miR-148a-5p to resist DTMUV. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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13 pages, 2499 KiB

Open AccessArticle

DENV2 Pseudoviral Particles with Unprocessed Capsid Protein Are Assembled and Infectious

by Jyoti Rana and Oscar R. Burrone

Viruses 2020, 12(1), 27; https://doi.org/10.3390/v12010027 - 25 Dec 2019

Cited by 3 | Viewed by 3232

Abstract

Proteolytic processing of flavivirus polyprotein is a uniquely controlled process. To date, the sequential cleavage of the capsid anchor sequence at the junction of C-PrM has been considered essential for the production of flaviviruses. In this study, we used two experimental approaches to [...] Read more.

Proteolytic processing of flavivirus polyprotein is a uniquely controlled process. To date, the sequential cleavage of the capsid anchor sequence at the junction of C-PrM has been considered essential for the production of flaviviruses. In this study, we used two experimental approaches to show the effect of unprocessed capsid on the production and infectivity of dengue virus 2 (DENV2) pseudoviral particles. The results showed that (1) both mature and unprocessed capsids of DENV2 were equally efficient in the viral RNA packaging and also in the assembly of infective particles; (2) DENV2 variants, in which the viral and host mediated cleavage of Ca peptide were independent, produced significantly higher levels of infective particles. Overall, this study demonstrated that unlike other flaviviruses, DENV2 capsid does not require a cleavable Ca sequence, and the sequential cleavage is not an obligatory requirement for the morphogenesis of infective pseudoviral particles. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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17 pages, 3185 KiB

Open AccessArticle

In Vivo Characterization of Tick-Borne Encephalitis Virus in Bank Voles (Myodes glareolus)

by Anna Michelitsch, Birke Andrea Tews, Christine Klaus, Malena Bestehorn-Willmann, Gerhard Dobler, Martin Beer and Kerstin Wernike

Viruses 2019, 11(11), 1069; https://doi.org/10.3390/v11111069 - 15 Nov 2019

Cited by 13 | Viewed by 3282

Abstract

Tick-borne encephalitis is the most important tick-transmitted zoonotic virus infection in Eurasia, causing severe neurological symptoms in humans. The causative agent, the tick-borne encephalitis virus (TBEV), circulates between ticks and a variety of mammalian hosts. To study the interaction between TBEV and one [...] Read more.

Tick-borne encephalitis is the most important tick-transmitted zoonotic virus infection in Eurasia, causing severe neurological symptoms in humans. The causative agent, the tick-borne encephalitis virus (TBEV), circulates between ticks and a variety of mammalian hosts. To study the interaction between TBEV and one of its suspected reservoir hosts, bank voles of the Western evolutionary lineage were inoculated subcutaneously with either one of eight TBEV strains or the related attenuated Langat virus, and were euthanized after 28 days. In addition, a subset of four strains was characterized in bank voles of the Carpathian linage. Six bank voles were inoculated per strain, and were housed together in groups of three with one uninfected in-contact animal each. Generally, most bank voles did not show any clinical signs over the course of infection. However, one infected bank vole died and three had to be euthanized prematurely, all of which had been inoculated with the identical TBEV strain (Battaune 17-H9, isolated in 2017 in Germany from a bank vole). All inoculated animals seroconverted, while none of the in-contact animals did. Viral RNA was detected via real-time RT-PCR in the whole blood samples of 31 out of 74 inoculated and surviving bank voles. The corresponding serum sample remained PCR-negative in nearly all cases (29/31). In addition, brain and/or spine samples tested positive in 11 cases, mostly correlating with a positive whole blood sample. Our findings suggest a good adaption of TBEV to bank voles, combining in most cases a low virulence phenotype with detectable virus replication and hinting at a reservoir host function of bank voles for TBEV. Full article

(This article belongs to the Special Issue Flavivirus Replication and Pathogenesis)

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18 pages, 3176 KiB

Open AccessArticle

A Dengue Virus Type 2 (DENV-2) NS4B-Interacting Host Factor, SERP1, Reduces DENV-2 Production by Suppressing Viral RNA Replication

by Jia-Ni Tian, Chi-Chen Yang, Chiu-Kai Chuang, Ming-Han Tsai, Ren-Huang Wu, Chiung-Tong Chen and Andrew Yueh

Viruses 2019, 11(9), 787; https://doi.org/10.3390/v11090787 - 27 Aug 2019

Cited by 10 | Viewed by 3961

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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15 pages, 3976 KiB

Open AccessArticle

Screening of Duck Tembusu Virus NS3 Interacting Host Proteins and Identification of Its Specific Interplay Domains

by Yawen Wang, Shuai Zhang, Yi Tang and Youxiang Diao

Viruses 2019, 11(8), 740; https://doi.org/10.3390/v11080740 - 12 Aug 2019

Cited by 7 | Viewed by 5108

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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16 pages, 3005 KiB

Open AccessArticle

Cellular Interleukin Enhancer-Binding Factor 2, ILF2, Inhibits Japanese Encephalitis Virus Replication In Vitro

by Xiaofang Cui, Ping Qian, Tingting Rao, Yanming Wei, Fang Zhao, Huawei Zhang, Huanchun Chen and Xiangmin Li

Viruses 2019, 11(6), 559; https://doi.org/10.3390/v11060559 - 17 Jun 2019

Cited by 8 | Viewed by 3837

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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32 pages, 2218 KiB

Open AccessReview

Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus

by Robin D.V. Kleinert, Eduardo Montoya-Diaz, Tanvi Khera, Kathrin Welsch, Birthe Tegtmeyer, Sebastian Hoehl, Sandra Ciesek and Richard J.P. Brown

Viruses 2019, 11(10), 960; https://doi.org/10.3390/v11100960 - 17 Oct 2019

Cited by 15 | Viewed by 7977

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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14 pages, 1252 KiB

Open AccessReview

Flavivirus RNA-Dependent RNA Polymerase Interacts with Genome UTRs and Viral Proteins to Facilitate Flavivirus RNA Replication

by YanPing Duan, Miao Zeng, Bowen Jiang, Wei Zhang, Mingshu Wang, Renyong Jia, Dekang Zhu, Mafeng Liu, Xinxin Zhao, Qiao Yang, Ying Wu, ShaQiu Zhang, YunYa Liu, Ling Zhang, YanLing Yu, Leichang Pan, Shun Chen and Anchun Cheng

Viruses 2019, 11(10), 929; https://doi.org/10.3390/v11100929 - 10 Oct 2019

Cited by 18 | Viewed by 4640

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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17 pages, 2355 KiB

Open AccessReview

Exploring the Reservoir Hosts of Tick-Borne Encephalitis Virus

by Anna Michelitsch, Kerstin Wernike, Christine Klaus, Gerhard Dobler and Martin Beer

Viruses 2019, 11(7), 669; https://doi.org/10.3390/v11070669 - 22 Jul 2019

Cited by 77 | Viewed by 7851

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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