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Viruses, Volume 11, Issue 3 (March 2019)

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Cover Story (view full-size image) Viruses exploit glycans for initial attachment to and subsequent infection of host cells. The host [...] Read more.
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Open AccessArticle The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV
Viruses 2019, 11(3), 303; https://doi.org/10.3390/v11030303
Received: 7 February 2019 / Revised: 22 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only [...] Read more.
La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only well-described CLR that recognizes LACV. In this study, we investigated the role of additional CLR/LACV interactions. To this end, we applied a flow-through chromatography method for the purification of LACV to perform an unbiased high-throughput screening of LACV with a CLR-hFc fusion protein library. Interestingly, the CARD9-associated CLRs Mincle, Dectin-1, and Dectin-2 were identified to strongly interact with LACV. Since CARD9 is a common adaptor protein for signaling via Mincle, Dectin-1, and Dectin-2, we performed LACV infection of Mincle−/− and CARD9−/− DCs. Mincle−/− and CARD9−/− DCs produced less amounts of proinflammatory cytokines, namely IL-6 and TNF-α, albeit no reduction of the LACV titer was observed. Together, novel CLR/LACV interactions were identified; however, the Mincle/CARD9 axis plays a limited role in early antiviral responses against LACV. Full article
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Open AccessReview IFN Signaling in Inflammation and Viral Infections: New Insights from Fish Models
Viruses 2019, 11(3), 302; https://doi.org/10.3390/v11030302
Received: 4 March 2019 / Revised: 22 March 2019 / Accepted: 23 March 2019 / Published: 26 March 2019
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Abstract
The overarching structure of the type I interferon (IFN) system is conserved across vertebrates. However, the variable numbers of whole genome duplication events during fish evolution offer opportunities for the expansion, diversification, and new functionalization of the genes that are involved in antiviral [...] Read more.
The overarching structure of the type I interferon (IFN) system is conserved across vertebrates. However, the variable numbers of whole genome duplication events during fish evolution offer opportunities for the expansion, diversification, and new functionalization of the genes that are involved in antiviral immunity. In this review, we examine how fish models provide new insights about the implication of virus-driven inflammation in immunity and hematopoiesis. Mechanisms that have been discovered in fish, such as the strong adjuvant effect of type I IFN that is used with DNA vaccination, constitute good models to understand how virus-induced inflammatory mechanisms can interfere with adaptive responses. We also comment on new discoveries regarding the role of pathogen-induced inflammation in the development and guidance of hematopoietic stem cells in zebrafish. These findings raise issues about the potential interferences of viral infections with the establishment of the immune system. Finally, the recent development of genome editing provides new opportunities to dissect the roles of the key players involved in the antiviral response in fish, hence enhancing the power of comparative approaches. Full article
(This article belongs to the Special Issue Viruses Ten-Year Anniversary)
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Open AccessArticle Zika Virus-Specific IgY Results Are Therapeutic Following a Lethal Zika Virus Challenge without Inducing Antibody-Dependent Enhancement
Viruses 2019, 11(3), 301; https://doi.org/10.3390/v11030301
Received: 1 March 2019 / Revised: 19 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
The Zika virus (ZIKV) is a newly emerged pathogen in the Western hemisphere. It was declared a global health emergency by the World Health Organization in 2016. There have been 223,477 confirmed cases, including 3720 congenital syndrome cases since 2015. ZIKV infection symptoms [...] Read more.
The Zika virus (ZIKV) is a newly emerged pathogen in the Western hemisphere. It was declared a global health emergency by the World Health Organization in 2016. There have been 223,477 confirmed cases, including 3720 congenital syndrome cases since 2015. ZIKV infection symptoms range from asymptomatic to Gullain–Barré syndrome and extensive neuropathology in infected fetuses. Passive and active vaccines have been unsuccessful in the protection from or the treatment of flaviviral infections due to antibody-dependent enhancement (ADE). ADE causes an increased viral load due to an increased monocyte opsonization by non-neutralizing, low-avidity antibodies from a previous dengue virus (DENV) infection or from a previous exposure to ZIKV. We have previously demonstrated that polyclonal avian IgY generated against whole-killed DENV-2 ameliorates DENV infection in mice while not inducing ADE. This is likely due to the inability of the Fc portion of IgY to bind to mammalian Fc receptors. We have shown here that ZIKV oligoclonal IgY is able to neutralize the virus in vitro and in IFNAR−/− mice. The concentration of ZIKV-specific IgY yielding 50% neutralization (NT50) was 25 µg/mL. The exposure of the ZIKV, prior to culture with ZIKV-specific IgY or 4G2 flavivirus-enveloped IgG, demonstrated that the ZIKV-specific IgY does not induce ADE. ZIKV IgY was protective in vivo when administered following a lethal ZIKV challenge in 3-week-old IFNAR−/− mice. We propose polyclonal ZIKV-specific IgY may provide a viable passive immunotherapy for a ZIKV infection without inducing ADE. Full article
(This article belongs to the Section Antivirals & Vaccines)
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Open AccessReview Innovation in Newcastle Disease Virus Vectored Avian Influenza Vaccines
Viruses 2019, 11(3), 300; https://doi.org/10.3390/v11030300
Received: 25 February 2019 / Revised: 19 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Highly pathogenic avian influenza (HPAI) and Newcastle disease are economically important avian diseases worldwide. Effective vaccination is critical to control these diseases in poultry. Live attenuated Newcastle disease virus (NDV) vectored vaccines have been developed for bivalent vaccination against HPAI viruses and NDV. [...] Read more.
Highly pathogenic avian influenza (HPAI) and Newcastle disease are economically important avian diseases worldwide. Effective vaccination is critical to control these diseases in poultry. Live attenuated Newcastle disease virus (NDV) vectored vaccines have been developed for bivalent vaccination against HPAI viruses and NDV. These vaccines have been generated by inserting the hemagglutinin (HA) gene of avian influenza virus into NDV genomes. In laboratory settings, several experimental NDV-vectored vaccines have protected specific pathogen-free chickens from mortality, clinical signs, and virus shedding against H5 and H7 HPAI viruses and NDV challenges. NDV-vectored H5 vaccines have been licensed for poultry vaccination in China and Mexico. Recently, an antigenically chimeric NDV vector has been generated to overcome pre-existing immunity to NDV in poultry and to provide early protection of poultry in the field. Prime immunization of one-day-old poults with a chimeric NDV vector followed by boosting with a conventional NDV vector has shown to protect broiler chickens against H5 HPAI viruses and a highly virulent NDV. This novel vaccination approach can provide efficient control of HPAI viruses in the field and facilitate poultry vaccination. Full article
(This article belongs to the Special Issue Avian Respiratory Viruses)
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Open AccessArticle Metagenomes of a Freshwater Charavirus from British Columbia Provide a Window into Ancient Lineages of Viruses
Viruses 2019, 11(3), 299; https://doi.org/10.3390/v11030299
Received: 3 March 2019 / Revised: 19 March 2019 / Accepted: 21 March 2019 / Published: 25 March 2019
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Abstract
Charophyte algae, not chlorophyte algae, are the ancestors of ‘higher plants’; hence, viruses infecting charophytes may be related to those that first infected higher plants. Streamwaters from British Columbia, Canada, yielded single-stranded RNA metagenomes of Charavirus canadensis (CV-Can), that are similar in genomic [...] Read more.
Charophyte algae, not chlorophyte algae, are the ancestors of ‘higher plants’; hence, viruses infecting charophytes may be related to those that first infected higher plants. Streamwaters from British Columbia, Canada, yielded single-stranded RNA metagenomes of Charavirus canadensis (CV-Can), that are similar in genomic architecture, length (9593 nt), nucleotide identity (63.4%), and encoded amino-acid sequence identity (53.0%) to those of Charavirus australis (CV-Aus). The sequences of their RNA-dependent RNA-polymerases (RdRp) resemble those found in benyviruses, their helicases those of hepaciviruses and hepegiviruses, and their coat-proteins (CP) those of tobamoviruses; all from the alphavirus/flavivirus branch of the ‘global RNA virome’. The 5’-terminus of the CV-Can genome, but not that of CV-Aus, is complete and encodes a methyltransferase domain. Comparisons of CP sequences suggests that Canadian and Australian charaviruses diverged 29–46 million years ago (mya); whereas, the CPs of charaviruses and tobamoviruses last shared a common ancestor 212 mya, and the RdRps of charaviruses and benyviruses 396 mya. CV-Can is sporadically abundant in low-nutrient freshwater rivers in British Columbia, where Chara braunii, a close relative of C. australis, occurs, and which may be its natural host. Charaviruses, like their hosts, are ancient and widely distributed, and thus provide a window to the viromes of early eukaryotes and, even, Archaea. Full article
(This article belongs to the Special Issue Plant Virus Ecology and Biodiversity)
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Open AccessArticle Functional RNA Structures in the 3′UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses
Viruses 2019, 11(3), 298; https://doi.org/10.3390/v11030298
Received: 1 March 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 24 March 2019
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Abstract
Untranslated regions (UTRs) of flaviviruses contain a large number of RNA structural elements involved in mediating the viral life cycle, including cyclisation, replication, and encapsidation. Here we report on a comparative genomics approach to characterize evolutionarily conserved RNAs in the 3UTR [...] Read more.
Untranslated regions (UTRs) of flaviviruses contain a large number of RNA structural elements involved in mediating the viral life cycle, including cyclisation, replication, and encapsidation. Here we report on a comparative genomics approach to characterize evolutionarily conserved RNAs in the 3 UTR of tick-borne, insect-specific and no-known-vector flaviviruses in silico. Our data support the wide distribution of previously experimentally characterized exoribonuclease resistant RNAs (xrRNAs) within tick-borne and no-known-vector flaviviruses and provide evidence for the existence of a cascade of duplicated RNA structures within insect-specific flaviviruses. On a broader scale, our findings indicate that viral 3 UTRs represent a flexible scaffold for evolution to come up with novel xrRNAs. Full article
(This article belongs to the Special Issue Virus Bioinformatics)
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Open AccessCommunication A Novel Hepacivirus in Wild Rodents from South America
Viruses 2019, 11(3), 297; https://doi.org/10.3390/v11030297
Received: 22 January 2019 / Revised: 11 March 2019 / Accepted: 18 March 2019 / Published: 24 March 2019
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Abstract
The Hepacivirus genus comprises single-stranded positive-sense RNA viruses within the family Flaviviridae. Several hepaciviruses have been identified in different mammals, including multiple rodent species in Africa, Asia, Europe, and North America. To date, no rodent hepacivirus has been identified in the South [...] Read more.
The Hepacivirus genus comprises single-stranded positive-sense RNA viruses within the family Flaviviridae. Several hepaciviruses have been identified in different mammals, including multiple rodent species in Africa, Asia, Europe, and North America. To date, no rodent hepacivirus has been identified in the South American continent. Here, we describe an unknown hepacivirus discovered during a metagenomic screen in Akodon montensis, Calomys tener, Oligoryzomys nigripes, Necromys lasiurus, and Mus musculus from São Paulo State, Brazil. Molecular detection of this novel hepacivirus by RT-PCR showed a frequency of 11.11% (2/18) in Oligoryzomys nigripes. This is the first identification of hepavivirus in sigmondonine rodents and in rodents from South America. In sum, our results expand the host range, viral diversity, and geographical distribution of the Hepacivirus genus. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle A Field Recombinant Strain Derived from Two Type 1 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-1) Modified Live Vaccines Shows Increased Viremia and Transmission in SPF Pigs
Viruses 2019, 11(3), 296; https://doi.org/10.3390/v11030296
Received: 28 January 2019 / Revised: 15 March 2019 / Accepted: 21 March 2019 / Published: 23 March 2019
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Abstract
In Europe, modified live vaccines (MLV) are commonly used to control porcine reproductive and respiratory syndrome virus (PRRSV) infection. However, they have been associated with safety issues such as reversion to virulence induced by mutation and/or recombination. On a French pig farm, we [...] Read more.
In Europe, modified live vaccines (MLV) are commonly used to control porcine reproductive and respiratory syndrome virus (PRRSV) infection. However, they have been associated with safety issues such as reversion to virulence induced by mutation and/or recombination. On a French pig farm, we identified a field recombinant strain derived from two PRRSV-1 MLV (MLV1). As a result, we aimed to evaluate its clinical, virological, and transmission parameters in comparison with both parental strains. Three groups with six pigs in each were inoculated with either one of the two MLV1s or with the recombinant strain; six contact pigs were then added into each inoculated group. The animals were monitored daily for 35 days post-inoculation (dpi) for clinical symptoms; blood samples and nasal swabs were collected twice a week. PRRS viral load in inoculated pigs of recombinant group was higher in serum, nasal swabs, and tonsils in comparison with both vaccine groups. The first viremic contact pig was detected as soon as 2 dpi in the recombinant group compared to 10 and 17 dpi for vaccine groups. Estimation of transmission parameters revealed fastest transmission and longest duration of infectiousness for recombinant group. Our in vivo study showed that the field recombinant strain derived from two MLV1s demonstrated high viremia, shedding and transmission capacities. Full article
(This article belongs to the Special Issue Porcine Viruses 2019)
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Open AccessReview Towards Inhaled Phage Therapy in Western Europe
Viruses 2019, 11(3), 295; https://doi.org/10.3390/v11030295
Received: 15 February 2019 / Revised: 12 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
The emergence of multidrug-resistant bacteria constitutes a great challenge for modern medicine, recognized by leading medical experts and politicians worldwide. Rediscovery and implementation of bacteriophage therapy by Western medicine might be one solution to the problem of increasing antibiotic failure. In some Eastern [...] Read more.
The emergence of multidrug-resistant bacteria constitutes a great challenge for modern medicine, recognized by leading medical experts and politicians worldwide. Rediscovery and implementation of bacteriophage therapy by Western medicine might be one solution to the problem of increasing antibiotic failure. In some Eastern European countries phage therapy is used for treating infectious diseases. However, while the European Medicines Agency (EMA) advised that the development of bacteriophage-based therapies should be expedited due to its significant potential, EMA emphasized that phages cannot be recommended for approval before efficacy and safety have been proven by appropriately designed preclinical and clinical trials. More evidence-based data is required, particularly in the areas of pharmacokinetics, repeat applications, immunological reactions to the application of phages as well as the interactions and effects on bacterial biofilms and organ-specific environments. In this brief review we summarize advantages and disadvantages of phage therapy and discuss challenges to the establishment of phage therapy as approved treatment for multidrug-resistant bacteria. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
Open AccessReview Chikungunya in Infants and Children: Is Pathogenesis Increasing?
Viruses 2019, 11(3), 294; https://doi.org/10.3390/v11030294
Received: 27 February 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
Chikungunya virus (CHIKV) was first extensively described in children during outbreaks in India and South Asia during the mid-1960s. Prior to the 2005 emergence of CHIKV on Reunion Island, CHIKV infection was usually described as a dengue-like illness with arthralgia in Africa and [...] Read more.
Chikungunya virus (CHIKV) was first extensively described in children during outbreaks in India and South Asia during the mid-1960s. Prior to the 2005 emergence of CHIKV on Reunion Island, CHIKV infection was usually described as a dengue-like illness with arthralgia in Africa and febrile hemorrhagic disease in Asia. Soon after the 2005 emergence, severe CNS consequences from vertical and perinatal transmission were described and as CHIKV continued to emerge in new areas over the next 10 years, severe manifestation of infection and sequelae were increasingly reported in infants and neonates. The following review describes the global reemergence and the syndromes of Chikungunya fever (CHIKF) in infants and children. The various manifestations of CHIKF are described and connected to the viral lineage that was documented in the area at the time the disease was described. The data show that certain manifestations of CHIKF occur with specific viral lineages and genetic motifs, which suggests that severe manifestations of CHIKF in the very young may be associated with the emergence of new viral lineages. Full article
(This article belongs to the Special Issue Chikungunya Virus and (Re-) Emerging Alphaviruses)
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Open AccessArticle Autophagy Promotes Infectious Particle Production of Mopeia and Lassa Viruses
Viruses 2019, 11(3), 293; https://doi.org/10.3390/v11030293
Received: 20 February 2019 / Revised: 14 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic [...] Read more.
Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic mechanisms that occur during the course of pathogenic arenavirus infection. We used a yeast two-hybrid approach to identify cell partners of MOPV and LASV Z matrix protein in which two autophagy adaptors were identified, NDP52 and TAX1BP1. Autophagy has emerged as an important cellular defense mechanism against viral infections but its role during arenavirus infection has not been shown. Here, we demonstrate that autophagy is transiently induced by MOPV, but not LASV, in infected cells two days after infection. Impairment of the early steps of autophagy significantly decreased the production of MOPV and LASV infectious particles, whereas a blockade of the degradative steps impaired only MOPV infectious particle production. Our study provides insights into the role played by autophagy during MOPV and LASV infection and suggests that this process could partially explain their different pathogenicity. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle The PB2 Polymerase Host Adaptation Substitutions Prime Avian Indonesia Sub Clade 2.1 H5N1 Viruses for Infecting Humans
Viruses 2019, 11(3), 292; https://doi.org/10.3390/v11030292
Received: 15 February 2019 / Revised: 21 March 2019 / Accepted: 22 March 2019 / Published: 22 March 2019
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Abstract
Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed [...] Read more.
Significantly higher numbers of human infections with H5N1 virus have occurred in Indonesia and Egypt, compared with other affected areas, and it is speculated that there are specific viral factors for human infection with avian H5N1 viruses in these locations. We previously showed PB2-K526R is present in 80% of Indonesian H5N1 human isolates, which lack the more common PB2-E627K substitution. Testing the hypothesis that this mutation may prime avian H5N1 virus for human infection, we showed that: (1) K526R is rarely found in avian influenza viruses but was identified in H5N1 viruses 2–3 years after the virus emerged in Indonesia, coincident with the emergence of H5N1 human infections in Indonesia; (2) K526R is required for efficient replication of Indonesia H5N1 virus in mammalian cells in vitro and in vivo and reverse substitution to 526K in human isolates abolishes this ability; (3) Indonesian H5N1 virus, which contains K526R-PB2, is stable and does not further acquire E627K following replication in infected mice; and (4) virus containing K526R-PB2 shows no fitness deficit in avian species. These findings illustrate an important mechanism in which a host adaptive mutation that predisposes avian H5N1 virus towards infecting humans has arisen with the virus becoming prevalent in avian species prior to human infections occurring. A similar mechanism is observed in the Qinghai-lineage H5N1 viruses that have caused many human cases in Egypt; here, E627K predisposes towards human infections. Surveillance should focus on the detection of adaptation markers in avian strains that prime for human infection. Full article
(This article belongs to the Special Issue Avian Respiratory Viruses)
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Open AccessArticle Differential Innate Immune Responses Elicited by Nipah Virus and Cedar Virus Correlate with Disparate In Vivo Pathogenesis in Hamsters
Viruses 2019, 11(3), 291; https://doi.org/10.3390/v11030291
Received: 25 February 2019 / Revised: 15 March 2019 / Accepted: 20 March 2019 / Published: 22 March 2019
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Abstract
Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens [...] Read more.
Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens of infected hamsters, a neutralizing antibody was produced in some hamsters within 8 days post-challenge, and no conspicuous signs of disease occurred. CedPV replicated to a similar magnitude as NiV-Bangladesh in type I IFN-deficient BHK-21 Syrian hamster fibroblasts but replicated 4 logs lower in type I IFN-competent primary Syrian hamster and human pulmonary endothelial cells, a principal target of henipaviruses. The coinfection of these cells with CedPV and NiV failed to rescue CedPV titers and did not diminish NiV titers, suggesting the replication machinery is virus-specific. Type I IFN response transcripts Ifna7, Ddx58, Stat1, Stat2, Ccl5, Cxcl10, Isg20, Irf7, and Iigp1 were all significantly elevated in CedPV-infected hamster endothelial cells, whereas Ifna7 and Iigp1 expression were significantly repressed during NiV infection. These results are consistent with the hypothesis that CedPV’s inability to counter the host type I IFN response may, in part, contribute to its lack of pathogenicity. Because NiV causes a fatal disease in Syrian hamsters with similarities to human disease, this model will provide valuable information about the pathogenic mechanisms of henipaviruses. Full article
(This article belongs to the Special Issue Viruses and Bats 2019)
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Open AccessReview Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as A Therapeutic Strategy for Alphaviral Disease
Viruses 2019, 11(3), 290; https://doi.org/10.3390/v11030290
Received: 28 February 2019 / Revised: 19 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
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Abstract
Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global [...] Read more.
Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined. Full article
(This article belongs to the Special Issue Viruses and Inflammation)
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Open AccessReview The Clinical Features, Pathogenesis and Methotrexate Therapy of Chronic Chikungunya Arthritis
Viruses 2019, 11(3), 289; https://doi.org/10.3390/v11030289
Received: 24 February 2019 / Revised: 18 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
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Abstract
Chikungunya fever (CHIKF) is an emerging viral infection that has spread widely, along with its Aedes vectors, throughout the tropics and beyond, causing explosive epidemics of acute illness and persistent disabling arthritis. The rheumatic symptoms associated with chikungunya virus (CHIKV) infection include polyarthralgia, [...] Read more.
Chikungunya fever (CHIKF) is an emerging viral infection that has spread widely, along with its Aedes vectors, throughout the tropics and beyond, causing explosive epidemics of acute illness and persistent disabling arthritis. The rheumatic symptoms associated with chikungunya virus (CHIKV) infection include polyarthralgia, polyarthritis, morning stiffness, joint edema, and erythema. Chronic CHIK arthritis (CCA) often causes severe pain and associated disability. The pathogenesis of CCA is not well understood. Proposed hypotheses include the persistence of a low level of replicating virus in the joints, the persistence of viral RNA in the synovium, and the induction of autoimmunity. In this review, we describe the main hypotheses of CCA pathogenesis, some of which support methotrexate (MTX) treatment which has been shown to be effective in preliminary studies in CCA. Full article
(This article belongs to the Special Issue Chikungunya Virus and (Re-) Emerging Alphaviruses)
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Open AccessReview Function, Architecture, and Biogenesis of Reovirus Replication Neoorganelles
Viruses 2019, 11(3), 288; https://doi.org/10.3390/v11030288
Received: 26 January 2019 / Revised: 17 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
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Abstract
Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release [...] Read more.
Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release of progeny particles. Reoviruses are common pathogens of mammals that have been linked to celiac disease and show promise for oncolytic applications. These viruses form nonenveloped, double-shelled virions that contain ten segments of double-stranded RNA. Replication organelles in reovirus-infected cells are nucleated by viral nonstructural proteins µNS and σNS. Both proteins partition the endoplasmic reticulum to form the matrix of these structures. The resultant membranous webs likely serve to anchor viral RNA–protein complexes for the replication of the reovirus genome and the assembly of progeny virions. Ongoing studies of reovirus replication organelles will advance our knowledge about the strategies used by viruses to commandeer host biosynthetic pathways and may expose new targets for therapeutic intervention against diverse families of pathogenic viruses. Full article
(This article belongs to the Special Issue Viruses Ten-Year Anniversary)
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Open AccessArticle Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus
Viruses 2019, 11(3), 287; https://doi.org/10.3390/v11030287
Received: 28 January 2019 / Revised: 4 March 2019 / Accepted: 18 March 2019 / Published: 21 March 2019
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Abstract
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of [...] Read more.
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessReview Caliciviridae Other Than Noroviruses
Viruses 2019, 11(3), 286; https://doi.org/10.3390/v11030286
Received: 18 January 2019 / Revised: 8 March 2019 / Accepted: 11 March 2019 / Published: 21 March 2019
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Abstract
Besides noroviruses, the Caliciviridae family comprises four other accepted genera: Sapovirus, Lagovirus, Vesivirus, and Nebovirus. There are six new genera proposed: Recovirus, Valovirus, Bavovirus, Nacovirus, Minovirus, and Salovirus. All Caliciviridae have closely related genome structures, but are genetically and antigenically [...] Read more.
Besides noroviruses, the Caliciviridae family comprises four other accepted genera: Sapovirus, Lagovirus, Vesivirus, and Nebovirus. There are six new genera proposed: Recovirus, Valovirus, Bavovirus, Nacovirus, Minovirus, and Salovirus. All Caliciviridae have closely related genome structures, but are genetically and antigenically highly diverse and infect a wide range of mammalian host species including humans. Recombination in nature is not infrequent for most of the Caliciviridae, contributing to their diversity. Sapovirus infections cause diarrhoea in pigs, humans and other mammalian hosts. Lagovirus infections cause systemic haemorrhagic disease in rabbits and hares, and vesivirus infections lead to lung disease in cats, vesicular disease in swine, and exanthema and diseases of the reproductive system in large sea mammals. Neboviruses are an enteric pathogen of cattle, differing from bovine norovirus. At present, only a few selected caliciviruses can be propagated in cell culture (permanent cell lines or enteroids), and for most of the cultivatable caliciviruses helper virus-free, plasmid only-based reverse genetics systems have been established. The replication cycles of the caliciviruses are similar as far as they have been explored: viruses interact with a multitude of cell surface attachment factors (glycans) and co-receptors (proteins) for adsorption and penetration, use cellular membranes for the formation of replication complexes and have developed mechanisms to circumvent innate immune responses. Vaccines have been developed against lagoviruses and vesiviruses, and are under development against human noroviruses. Full article
(This article belongs to the Special Issue Noroviruses)
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Open AccessArticle Initial Characterization of the Epstein–Barr Virus BSRF1 Gene Product
Viruses 2019, 11(3), 285; https://doi.org/10.3390/v11030285
Received: 21 February 2019 / Revised: 18 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
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Abstract
Epstein–Barr virus (EBV) is a ubiquitous virus that causes infectious mononucleosis and several types of cancer, such as Burkitt lymphoma, T/NK-cell lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, it encodes more than 80 genes, many of which have not been characterized. EBV Bam [...] Read more.
Epstein–Barr virus (EBV) is a ubiquitous virus that causes infectious mononucleosis and several types of cancer, such as Burkitt lymphoma, T/NK-cell lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, it encodes more than 80 genes, many of which have not been characterized. EBV BamHI S rightward reading frame 1 (BSRF1) encodes a tegument protein that, unlike its homologs herpes simplex virus unique long 51 (UL51) and human cytomegalovirus UL71, has not been extensively investigated. To examine the role of BSRF1, we prepared knockout and revertant strains using the bacterial artificial chromosome system. Unexpectedly, the disruption of the gene had little or no effect on EBV lytic replication and the transformation of primary B cells. However, the knockdown of BSRF1 in B95-8 cells decreased progeny production. An immunofluorescence assay revealed that BSRF1 localized to the Golgi apparatus in the cytoplasm, as did its homologs. BSRF1 also associated with BamHI G leftward reading frame 3.5 (BGLF3.5), BamHI B rightward reading frame 2 (BBRF2), and BamHI A leftward reading frame 1 (BALF1), and BALF1 was incorporated into the tegument fraction with BSRF1. Taken together, our results indicate that BSRF1 plays a role in secondary envelopment or virion egress in the cytoplasm, as do its homolog genes. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Broad Bactericidal Activity of the Myoviridae Bacteriophage Lysins LysAm24, LysECD7, and LysSi3 against Gram-Negative ESKAPE Pathogens
Viruses 2019, 11(3), 284; https://doi.org/10.3390/v11030284
Received: 20 December 2018 / Revised: 18 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
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Abstract
The extremely rapid spread of multiple-antibiotic resistance among Gram-negative pathogens threatens to move humankind into the so-called “post-antibiotic era” in which the most efficient and safe antibiotics will not work. Bacteriophage lysins represent promising alternatives to antibiotics, as they are capable of digesting [...] Read more.
The extremely rapid spread of multiple-antibiotic resistance among Gram-negative pathogens threatens to move humankind into the so-called “post-antibiotic era” in which the most efficient and safe antibiotics will not work. Bacteriophage lysins represent promising alternatives to antibiotics, as they are capable of digesting bacterial cell wall peptidoglycans to promote their osmotic lysis. However, relatively little is known regarding the spectrum of lysin bactericidal activity against Gram-negative bacteria. In this study, we present the results of in vitro activity assays of three putative and newly cloned Myoviridae bacteriophage endolysins (LysAm24, LysECD7, and LysSi3). The chosen proteins represent lysins with diverse domain organization (single-domain vs. two-domain) and different predicted mechanisms of action (lysozyme vs. peptidase). The enzymes were purified, and their properties were characterized. The enzymes were tested against a panel of Gram-negative clinical bacterial isolates comprising all Gram-negative representatives of the ESKAPE group. Despite exhibiting different structural organizations, all of the assayed lysins were shown to be capable of lysing Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Salmonella typhi strains. Less than 50 μg/mL was enough to eradicate growing cells over more than five orders of magnitude. Thus, LysAm24, LysECD7, and LysSi3 represent promising therapeutic agents for drug development. Full article
(This article belongs to the Special Issue Biotechnological Applications of Phage and Phage-Derived Proteins)
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Open AccessHypothesis RNA Back and Forth: Looking through Ribozyme and Viroid Motifs
Viruses 2019, 11(3), 283; https://doi.org/10.3390/v11030283
Received: 27 February 2019 / Revised: 14 March 2019 / Accepted: 18 March 2019 / Published: 21 March 2019
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Abstract
Current cellular facts allow us to follow the link from chemical to biochemical metabolites, from the ancient to the modern world. In this context, the “RNA world” hypothesis proposes that early in the evolution of life, the ribozyme was responsible for the storage [...] Read more.
Current cellular facts allow us to follow the link from chemical to biochemical metabolites, from the ancient to the modern world. In this context, the “RNA world” hypothesis proposes that early in the evolution of life, the ribozyme was responsible for the storage and transfer of genetic information and for the catalysis of biochemical reactions. Accordingly, the hammerhead ribozyme (HHR) and the hairpin ribozyme belong to a family of endonucleolytic RNAs performing self-cleavage that might occur during replication. Furthermore, regarding the widespread occurrence of HHRs in several genomes of modern organisms (from mammals to small parasites and elsewhere), these small ribozymes have been regarded as living fossils of a primitive RNA world. They fold into 3D structures that generally require long-range intramolecular interactions to adopt the catalytically active conformation under specific physicochemical conditions. By studying viroids as plausible remains of ancient RNA, we recently demonstrated that they replicate in non-specific hosts, emphasizing their adaptability to different environments, which enhanced their survival probability over the ages. All these results exemplify ubiquitous features of life. Those are the structural and functional versatility of small RNAs, ribozymes, and viroids, as well as their diversity and adaptability to various extreme conditions. All these traits must have originated in early life to generate novel RNA populations. Full article
(This article belongs to the Special Issue Viroid-2018: International Conference on Viroids and Viroid-Like RNAs)
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Open AccessArticle A Single V672F Substitution in the Spike Protein of Field-Isolated PEDV Promotes Cell–Cell Fusion and Replication in VeroE6 Cells
Viruses 2019, 11(3), 282; https://doi.org/10.3390/v11030282
Received: 6 February 2019 / Revised: 15 March 2019 / Accepted: 19 March 2019 / Published: 20 March 2019
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Abstract
While porcine epidemic diarrhea virus (PEDV) infects and replicates in enterocytes lining villi of neonatal piglets with high efficiency, naturally isolated variants typically grow poorly in established cell lines, unless adapted by multiple passages. Cells infected with most cell-adapted PEDVs usually displayed large [...] Read more.
While porcine epidemic diarrhea virus (PEDV) infects and replicates in enterocytes lining villi of neonatal piglets with high efficiency, naturally isolated variants typically grow poorly in established cell lines, unless adapted by multiple passages. Cells infected with most cell-adapted PEDVs usually displayed large syncytia, a process triggered by the spike protein (S). To identify amino acids responsible for S-mediated syncytium formation, we constructed and characterized chimeric S proteins of the cell-adapted variant, YN144, in which the receptor binding domain (RBD) and S1/S2 cleavage site were replaced with those of a poorly culturable field isolate (G2). We demonstrated that the RBD, not the S1/S2 cleavage site, is critical for syncytium formation mediated by chimeric S proteins. Further mutational analyses revealed that a single mutation at the amino acid residue position 672 (V672F) could enable the chimeric S with the entire RBD derived from the G2 strain to trigger large syncytia. Moreover, recombinant PEDV viruses bearing S of the G2 strain with the single V672F substitution could induce extensive syncytium formation and replicate efficiently in VeroE6 cells stably expressing porcine aminopeptidase N (VeroE6-APN). Interestingly, we also demonstrated that while the V672F mutation is critical for the syncytium formation in VeroE6-APN cells, it exerts a minimal effect in Huh-7 cells, thereby suggesting the difference in receptor preference of PEDV among host cells. Full article
(This article belongs to the Special Issue Porcine Viruses 2019)
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Open AccessCommunication Hepatitis A Strain Linked to the European Outbreaks During Gay Events between 2016 and 2017, Identified in a Brazilian Homosexual Couple in 2017
Viruses 2019, 11(3), 281; https://doi.org/10.3390/v11030281
Received: 28 December 2018 / Revised: 27 February 2019 / Accepted: 13 March 2019 / Published: 20 March 2019
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Abstract
Hepatitis A virus (HAV) outbreaks among men who have sex with men (MSM) have been reported worldwide and associated primarily with sexual transmission through oral-anal sex. Here, we provide the molecular and evolutionary description of a European strain, linked to HAV outbreaks among [...] Read more.
Hepatitis A virus (HAV) outbreaks among men who have sex with men (MSM) have been reported worldwide and associated primarily with sexual transmission through oral-anal sex. Here, we provide the molecular and evolutionary description of a European strain, linked to HAV outbreaks among MSM, detected in a Brazilian homosexual couple. Bayesian analysis provided evidence that the viral isolates were introduced in Brazil from Spain between the end of 2016 and the beginning of 2017. Full article
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Open AccessReview Host Determinants of MERS-CoV Transmission and Pathogenesis
Viruses 2019, 11(3), 280; https://doi.org/10.3390/v11030280
Received: 1 March 2019 / Revised: 11 March 2019 / Accepted: 13 March 2019 / Published: 19 March 2019
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Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen that causes respiratory infection in humans, ranging from asymptomatic to severe pneumonia. In dromedary camels, the virus only causes a mild infection but it spreads efficiently between animals. Differences in the behavior of [...] Read more.
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic pathogen that causes respiratory infection in humans, ranging from asymptomatic to severe pneumonia. In dromedary camels, the virus only causes a mild infection but it spreads efficiently between animals. Differences in the behavior of the virus observed between individuals, as well as between humans and dromedary camels, highlight the role of host factors in MERS-CoV pathogenesis and transmission. One of these host factors, the MERS-CoV receptor dipeptidyl peptidase-4 (DPP4), may be a critical determinant because it is variably expressed in MERS-CoV-susceptible species as well as in humans. This could partially explain inter- and intraspecies differences in the tropism, pathogenesis, and transmissibility of MERS-CoV. In this review, we explore the role of DPP4 and other host factors in MERS-CoV transmission and pathogenesis—such as sialic acids, host proteases, and interferons. Further characterization of these host determinants may potentially offer novel insights to develop intervention strategies to tackle ongoing outbreaks. Full article
(This article belongs to the Special Issue MERS-CoV)
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Open AccessCommunication A Novel Orthohepadnavirus Identified in a Dead Maxwell’s Duiker (Philantomba maxwellii) in Taï National Park, Côte d’Ivoire
Viruses 2019, 11(3), 279; https://doi.org/10.3390/v11030279
Received: 28 February 2019 / Revised: 11 March 2019 / Accepted: 16 March 2019 / Published: 19 March 2019
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Abstract
New technologies enable viral discovery in a diversity of hosts, providing insights into viral evolution. We used one such approach, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform, on 21 samples originating from six dead Maxwell’s duikers (Philantomba maxwellii) from [...] Read more.
New technologies enable viral discovery in a diversity of hosts, providing insights into viral evolution. We used one such approach, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform, on 21 samples originating from six dead Maxwell’s duikers (Philantomba maxwellii) from Taï National Park, Côte d’Ivoire. We detected the presence of an orthohepadnavirus in one animal and characterized its 3128 bp genome. The highest viral copy numbers were detected in the spleen, followed by the lung, blood, and liver, with the lowest copy numbers in the kidney and heart; the virus was not detected in the jejunum. Viral copy numbers in the blood were in the range known from humans with active chronic infections leading to liver histolytic damage, suggesting this virus could be pathogenic in duikers, though many orthohepadnaviruses appear to be apathogenic in other hosts, precluding a formal test of this hypothesis. The virus was not detected in 29 other dead duiker samples from the Côte d’Ivoire and Central African Republic, suggesting either a spillover event or a low prevalence in these populations. Phylogenetic analysis placed the virus as a divergent member of the mammalian clade of orthohepadnaviruses, though its relationship to other orthohepadnaviruses remains uncertain. This represents the first orthohepadnavirus described in an artiodactyl. We have tentatively named this new member of the genus Orthohepadnavirus (family Hepadnaviridae), Taï Forest hepadnavirus. Further studies are needed to determine whether it, or some close relatives, are present in a broader range of artiodactyls, including livestock. Full article
(This article belongs to the Section Animal Viruses)
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Open AccessArticle Early Transcriptional Response to DNA Virus Infection in Sclerotinia sclerotiorum
Viruses 2019, 11(3), 278; https://doi.org/10.3390/v11030278
Received: 22 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
We previously determined that virions of Sclerotinia sclerotiorum hypovirulence associated DNA virus 1 (SsHADV-1) could directly infect hyphae of Sclerotinia sclerotiorum, resulting in hypovirulence of the fungal host. However, the molecular mechanisms of SsHADV-1 virions disruption of the fungal cell wall barrier [...] Read more.
We previously determined that virions of Sclerotinia sclerotiorum hypovirulence associated DNA virus 1 (SsHADV-1) could directly infect hyphae of Sclerotinia sclerotiorum, resulting in hypovirulence of the fungal host. However, the molecular mechanisms of SsHADV-1 virions disruption of the fungal cell wall barrier and entrance into the host cell are still unclear. To investigate the early response of S. sclerotiorum to SsHADV-1 infection, S. sclerotiorum hyphae were inoculated with purified SsHADV-1 virions. The pre- and post-infection hyphae were collected at one–three hours post-inoculation for transcriptome analysis. Further, bioinformatic analysis showed that differentially expressed genes (DEGs) regulated by SsHADV-1 infection were identified in S. sclerotiorum. In total, 187 genes were differentially expressed, consisting of more up-regulated (114) than down-regulated (73) genes. The identified DEGs were involved in several important pathways. Metabolic processes, biosynthesis of antibiotics, and secondary metabolites were the most affected categories in S. sclerotiorum upon SsHADV-1 infection. Cell structure analysis suggested that 26% of the total DEGs were related to membrane tissues. Furthermore, 10 and 27 DEGs were predicted to be located in the cell membrane and mitochondria, respectively. Gene ontology enrichment analyses of the DEGs were performed, followed by functional annotation of the genes. Interestingly, one third of the annotated functional DEGs could be involved in the Ras-small G protein signal transduction pathway. These results revealed that SsHADV-1 virions may be able to bind host membrane proteins and influence signal transduction through Ras-small G protein-coupled receptors during early infection, providing new insight towards the molecular mechanisms of virions infection in S. sclerotiorum. Full article
(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)
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Open AccessArticle Protection of Phage Applications in Crop Production: A Patent Landscape
Viruses 2019, 11(3), 277; https://doi.org/10.3390/v11030277
Received: 19 February 2019 / Revised: 14 March 2019 / Accepted: 16 March 2019 / Published: 19 March 2019
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Abstract
In agriculture, the prevention and treatment of bacterial infections represents an increasing challenge. Traditional (chemical) methods have been restricted to ensure public health and to limit the occurrence of resistant strains. Bacteriophages could be a sustainable alternative. A major hurdle towards the commercial [...] Read more.
In agriculture, the prevention and treatment of bacterial infections represents an increasing challenge. Traditional (chemical) methods have been restricted to ensure public health and to limit the occurrence of resistant strains. Bacteriophages could be a sustainable alternative. A major hurdle towards the commercial implementation of phage-based biocontrol strategies concerns aspects of regulation and intellectual property protection. Within this study, two datasets have been composed to analyze both scientific publications and patent documents and to get an idea on the focus of research and development (R&D) by means of an abstract and claim analysis. A total of 137 papers and 49 patent families were found from searching public databases, with their numbers increasing over time. Within this dataset, the majority of the patent documents were filed by non-profit organizations in Asia. There seems to be a good correlation between the papers and patent documents in terms of targeted bacterial genera. Furthermore, granted patents seem to claim rather broad and cover methods of treatment. This review shows that there is indeed growing publishing and patenting activity concerning phage biocontrol. Targeted research is needed to further stimulate the exploration of phages within integrated pest management strategies and to deal with bacterial infections in crop production. Full article
(This article belongs to the Special Issue Hurdles for Phage Therapy (PT) to Become a Reality)
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Open AccessBrief Report Localization of Frog Virus 3 Conserved Viral Proteins 88R, 91R, and 94L
Viruses 2019, 11(3), 276; https://doi.org/10.3390/v11030276
Received: 11 February 2019 / Revised: 28 February 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
The characterization of the function of conserved viral genes is central to developing a greater understanding of important aspects of viral replication or pathogenesis. A comparative genomic analysis of the iridoviral genomes identified 26 core genes conserved across the family Iridoviridae. Three [...] Read more.
The characterization of the function of conserved viral genes is central to developing a greater understanding of important aspects of viral replication or pathogenesis. A comparative genomic analysis of the iridoviral genomes identified 26 core genes conserved across the family Iridoviridae. Three of those conserved genes have no defined function; these include the homologs of frog virus 3 (FV3) open reading frames (ORFs) 88R, 91R, and 94L. Conserved viral genes that have been previously identified are known to participate in a number of viral activities including: transcriptional regulation, DNA replication/repair/modification/processing, protein modification, and viral structural proteins. To begin to characterize the conserved FV3 ORFs 88R, 91R, and 94L, we cloned the genes and determined their intracellular localization. We demonstrated that 88R localizes to the cytoplasm of the cell while 91R localizes to the nucleus and 94L localizes to the endoplasmic reticulum (ER). Full article
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Open AccessArticle Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors
Viruses 2019, 11(3), 275; https://doi.org/10.3390/v11030275
Received: 18 February 2019 / Revised: 14 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, [...] Read more.
Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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Open AccessReview Ebola Virus Entry: From Molecular Characterization to Drug Discovery
Viruses 2019, 11(3), 274; https://doi.org/10.3390/v11030274
Received: 20 February 2019 / Revised: 15 March 2019 / Accepted: 16 March 2019 / Published: 19 March 2019
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Abstract
Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family. The recent large outbreak of EVD in Western Africa (2013–2016) highlighted the worldwide threat represented by [...] Read more.
Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family. The recent large outbreak of EVD in Western Africa (2013–2016) highlighted the worldwide threat represented by the disease and its impact on global public health and the economy. The development of highly needed anti-Ebola virus antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, allowing to screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to study Ebola virus entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus-like particles, tremendously boosted both our knowledge of the viral life cycle and the identification of promising antiviral compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD. Full article
(This article belongs to the collection Advances in Ebolavirus, Marburgvirus, and Cuevavirus Research)
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