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Pathogens
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Current Advances in Flavivirus Research
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Current Advances in Flavivirus Research

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 35590

Special Issue Editors

Dr. Mukesh Kumar

E-Mail Website
Guest Editor
Department of Biology, Georgia State University, Atlanta, GA 30302, USA
Interests: infectious diseases; COVID-19; West Nile virus encephalitis; Zika virus
Dr. Ok Sarah Shin

E-Mail Website
Guest Editor
College of Medicine, Korea University, Seoul, Korea
Interests: host–pathogen interactions; innate immunity; virus-induced cell death; immune evasion; Zika virus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Infectious diseases have gained importance as a significant threat to public health following the recent outbreaks of arthropod-transmitted (arboviruses) in the Western hemisphere. Members of flavivirus genus are the most important arthropod-borne viruses causing disease in humans. This genus includes pathogens of public health importance, including the West Nile virus (WNV), Japanese encephalitis virus (JEV), dengue virus (DENV), and Zika virus (ZIKV). Flaviviruses continue to spread and cause human disease in new areas of the world. With the recent outbreaks of Zika and yellow fever virus infections, the interest in these arthropod-borne viruses is exceptionally high. In the last few years, genomic and molecular investigations have established a remarkable progress on the pathogenic mechanisms of flavivirus infections using in vitro and in vivo models. Despite tremendous research efforts, though, there are yet to be clinically approved vaccines or therapeutic treatments available to combat the flavivirus infections. The lack of specific therapeutics for flavivirus infection imparts a pressing need to identify the viral and host factors in flavivirus replication and disease outcome.

In this Special Issue, we aim to assemble a collection of research papers and reviews that highlight critical advancements in our understanding of flavivirus pathogenesis and countermeasure development. Of particular interest are the immune responses to flavivirus infection, virus–host cell interactions, vector–host interactions, novel discoveries in flavivirus pathogenesis, vaccine development, and antiviral development. We look forward to your submissions.

Dr. Mukesh Kumar
Dr. Ok Sarah Shin
Guest Editors

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 submissions that pass pre-check are 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. Pathogens 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 2200 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
  • Host–virus interaction
  • Disease pathogenesis
  • Immune modulation
  • Immune evasions
  • Virus-induced cell death
  • Transcriptomic anaylsis

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Published Papers (6 papers)

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Research

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13 pages, 3574 KiB  
Article
Zika Virus-Induction of the Suppressor of Cytokine Signaling 1/3 Contributes to the Modulation of Viral Replication
by Rak-Kyun Seong, Jae Kyung Lee and Ok Sarah Shin
Pathogens 2020, 9(3), 163; https://doi.org/10.3390/pathogens9030163 - 27 Feb 2020
Cited by 31 | Viewed by 3306
Abstract
Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged and caused global outbreaks since 2007. Although ZIKV proteins have been shown to suppress early anti-viral innate immune responses, little is known about the exact mechanisms. This study demonstrates that infection with either [...] Read more.
Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged and caused global outbreaks since 2007. Although ZIKV proteins have been shown to suppress early anti-viral innate immune responses, little is known about the exact mechanisms. This study demonstrates that infection with either the African or Asian lineage of ZIKV leads to a modulated expression of suppressor of cytokine signaling (SOCS) genes encoding SOCS1 and SOCS3 in the following cell models: A549 human lung adenocarcinoma cells; JAr human choriocarcinoma cells; human neural progenitor cells. Studies of viral gene expression in response to SOCS1 or SOCS3 demonstrated that the knockdown of these SOCS proteins inhibited viral NS5 or ZIKV RNA expression, whereas overexpression resulted in an increased expression. Moreover, the overexpression of SOCS1 or SOCS3 inhibited the retinoic acid-inducible gene-I-like receptor-mediated activation of both type I and III interferon pathways. These results imply that SOCS upregulation following ZIKV infection modulates viral replication, possibly via the regulation of anti-viral innate immune responses. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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10 pages, 1625 KiB  
Communication
Inactivation of Zika Virus by Photoactive Iodonaphthyl Azide Preserves Immunogenic Potential of the Virus
by Amy L. Austin, Bianca Galasso, Caitlin Nickens, Barbara Knollmann-Ritschel and Anuj Sharma
Pathogens 2019, 8(4), 188; https://doi.org/10.3390/pathogens8040188 - 12 Oct 2019
Cited by 3 | Viewed by 3389
Abstract
Zika virus’s (ZIKV) emergence as a pathogen of significant public health importance has accelerated efforts to develop a ZIKV vaccine. To date, the need for an effective ZIKV vaccine is unmet. In this study, we report inactivation of ZIKV using a hydrophobic photoactive [...] Read more.
Zika virus’s (ZIKV) emergence as a pathogen of significant public health importance has accelerated efforts to develop a ZIKV vaccine. To date, the need for an effective ZIKV vaccine is unmet. In this study, we report inactivation of ZIKV using a hydrophobic photoactive compound: 1, 5 iodonaphthyl azide (INA). 50 and 100 µM of INA completely inactivated ZIKV (INA-ZIKV). Western blot and ELISA analysis show some loss of the binding capacity of INA-iZIKV to anti-ZIKV monoclonal antibodies; however, immunization of mice with INA-iZIKV demonstrated seroconversion and ZIKV-neutralizing antibody response. RNA isolated from INA-iZIKV did not induce productive infection in Vero cells, suggesting inactivation of ZIKV RNA. These results suggest that in the absence of an approved ZIKV vaccine, INA-iZIKV can be pursued as a viable ZIKV vaccine candidate. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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Review

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48 pages, 5860 KiB  
Review
Adaptive Immunity to Dengue Virus: Slippery Slope or Solid Ground for Rational Vaccine Design?
by Lucas Wilken and Guus F. Rimmelzwaan
Pathogens 2020, 9(6), 470; https://doi.org/10.3390/pathogens9060470 - 15 Jun 2020
Cited by 13 | Viewed by 10864
Abstract
The four serotypes of dengue virus are the most widespread causes of arboviral disease, currently placing half of the human population at risk of infection. Pre-existing immunity to one dengue virus serotype can predispose to severe disease following secondary infection with a different [...] Read more.
The four serotypes of dengue virus are the most widespread causes of arboviral disease, currently placing half of the human population at risk of infection. Pre-existing immunity to one dengue virus serotype can predispose to severe disease following secondary infection with a different serotype. The phenomenon of immune enhancement has complicated vaccine development and likely explains the poor long-term safety profile of a recently licenced dengue vaccine. Therefore, alternative vaccine strategies should be considered. This review summarises studies dissecting the adaptive immune responses to dengue virus infection and (experimental) vaccination. In particular, we discuss the roles of (i) neutralising antibodies, (ii) antibodies to non-structural protein 1, and (iii) T cells in protection and pathogenesis. We also address how these findings could translate into next-generation vaccine approaches that mitigate the risk of enhanced dengue disease. Finally, we argue that the development of a safe and efficacious dengue vaccine is an attainable goal. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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18 pages, 767 KiB  
Review
Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication
by Aarón Oyarzún-Arrau, Luis Alonso-Palomares, Fernando Valiente-Echeverría, Fabiola Osorio and Ricardo Soto-Rifo
Pathogens 2020, 9(3), 158; https://doi.org/10.3390/pathogens9030158 - 25 Feb 2020
Cited by 6 | Viewed by 5274
Abstract
Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by [...] Read more.
Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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12 pages, 749 KiB  
Review
Importance of Zika Virus NS5 Protein for Viral Replication
by Hesham Elshahawi, Sharifah Syed Hassan and Vinod Balasubramaniam
Pathogens 2019, 8(4), 169; https://doi.org/10.3390/pathogens8040169 - 30 Sep 2019
Cited by 29 | Viewed by 5725
Abstract
Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by [...] Read more.
Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by more severe outbreaks in French Polynesia (2013) and Brazil (2015), which significantly increased both Guillain-Barre syndrome and microcephaly cases. No current vaccines or treatments are available, however, recent studies have taken interest in the NS5 protein which encodes both the viral methyltransferase and RNA-dependent RNA polymerase. This makes it important for viral replication alongside other important functions such as inhibiting the innate immune system thus ensuring virus survival and replication. Structural studies can help design inhibitors, while biochemical studies can help understand the various mechanisms utilized by NS5 thus counteracting them might inhibit or abolish the viral infection. Drug repurposing targeting the NS5 protein has also proven to be an effective tool since hundreds of thousands of compounds can be screened therefore saving time and resources, moreover information on these compounds might already be available especially if they are used to treat other ailments. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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Graphical abstract

10 pages, 1001 KiB  
Review
Role of Endoplasmic Reticulum-Associated Proteins in Flavivirus Replication and Assembly Complexes
by Hussin A. Rothan and Mukesh Kumar
Pathogens 2019, 8(3), 148; https://doi.org/10.3390/pathogens8030148 - 12 Sep 2019
Cited by 32 | Viewed by 6231
Abstract
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER [...] Read more.
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER multiprotein complexes as vital factors for flavivirus replication. The detailed mechanisms of the role of ER complexes in flavivirus replication are still largely elusive. This review highlights the fact that the ER multiprotein complexes are crucial for the formation of flavivirus replication and assembly complexes, and the ER complexes could be considered as a target for developing successful broad-spectrum anti-flavivirus drugs. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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