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18 pages, 5924 KiB

Open AccessArticle

TNF-Mediated Inhibition of Classical Swine Fever Virus Replication Is IRF1-, NF-κB- and JAK/STAT Signaling-Dependent

by Matthias Liniger, Markus Gerber, Sandra Renzullo, Obdulio García-Nicolás and Nicolas Ruggli

Viruses 2021, 13(10), 2017; https://doi.org/10.3390/v13102017 - 7 Oct 2021

Cited by 10 | Viewed by 3143

Abstract

The sera from pigs infected with virulent classical swine fever virus (CSFV) contain substantial amounts of tumor necrosis factor (TNF), a prototype proinflammatory cytokine with pleiotropic activities. TNF limits the replication of CSFV in cell culture. In order to investigate the signaling involved [...] Read more.

The sera from pigs infected with virulent classical swine fever virus (CSFV) contain substantial amounts of tumor necrosis factor (TNF), a prototype proinflammatory cytokine with pleiotropic activities. TNF limits the replication of CSFV in cell culture. In order to investigate the signaling involved in the antiviral activity of TNF, we employed small-molecule inhibitors to interfere specifically with JAK/STAT and NF-κB signaling pathways in near-to-primary endothelial PEDSV.15 cells. In addition, we knocked out selected factors of the interferon (IFN) induction and signaling pathways using CRISPR/Cas9. We found that the anti-CSFV effect of TNF was sensitive to JAK/STAT inhibitors, suggesting that TNF induces IFN signaling. Accordingly, we observed that the antiviral effect of TNF was dependent on intact type I IFN signaling as PEDSV.15 cells with the disrupted type I IFN receptor lost their capacity to limit the replication of CSFV after TNF treatment. Consequently, we examined whether TNF activates the type I IFN induction pathway. With genetically modified PEDSV.15 cells deficient in functional interferon regulatory factor 1 or 3 (IRF1 or IRF3), we observed that the anti-CSFV activity exhibited by TNF was dependent on IRF1, whereas IRF3 was dispensable. This was distinct from the lipopolysaccharide (LPS)-driven antiviral effect that relied on both IRF1 and IRF3. In agreement with the requirement of IRF1 to induce TNF- and LPS-mediated antiviral effects, intact IRF1 was also essential for TNF- and LPS-mediated induction of IFN-β mRNA, while the activation of NF-κB was not dependent on IRF1. Nevertheless, NF-κB activation was essential for the TNF-mediated antiviral effect. Finally, we observed that CSFV failed to counteract the TNF-mediated induction of the IFN-β mRNA in PEDSV.15 cells, suggesting that CSFV does not interfere with IRF1-dependent signaling. In summary, we report that the proinflammatory cytokine TNF limits the replication of CSFV in PEDSV.15 cells by specific induction of an IRF1-dependent antiviral type I IFN response. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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18 pages, 1968 KiB

Open AccessArticle

Identification of a Common Conformational Epitope on the Glycoprotein E2 of Classical Swine Fever Virus and Border Disease Virus

by Yu-Liang Huang, Denise Meyer, Alexander Postel, Kuo-Jung Tsai, Hsin-Meng Liu, Chia-Huei Yang, Yu-Chun Huang, Nicholas Berkley, Ming-Chung Deng, Fun-In Wang, Paul Becher, Helen Crooke and Chia-Yi Chang

Viruses 2021, 13(8), 1655; https://doi.org/10.3390/v13081655 - 20 Aug 2021

Cited by 10 | Viewed by 3628

Abstract

Classical swine fever virus (CSFV) shares high structural and antigenic homology with bovine viral diarrhea virus (BVDV) and border disease virus (BDV). Because all three viruses can infect swine and elicit cross-reactive antibodies, it is necessary to differentiate among them with regard to [...] Read more.

Classical swine fever virus (CSFV) shares high structural and antigenic homology with bovine viral diarrhea virus (BVDV) and border disease virus (BDV). Because all three viruses can infect swine and elicit cross-reactive antibodies, it is necessary to differentiate among them with regard to serological diagnosis of classical swine fever. To understand the mechanism of cross-reactivity, it is important to define common or specific epitopes of these viruses. For this purpose, epitope mapping of six monoclonal antibodies (mAbs) was performed using recombinant expressed antigenic domains of CSFV and BDV E2 proteins. One CSFV-specific conformational epitope and one CSFV and BDV common epitope within domain B/C of E2 were identified. Site-directed mutagenesis confirmed that residues G725 and V738/I738 of the CSFV-specific epitope and P709/L709 and E713 of the second epitope are important for mAbs binding. Infection of CSFV in porcine cells was significantly reduced after pre-incubation of the cells with the domain B/C of E2 or after pre-incubation of CSFV with the mAbs detecting domain B/C. 3D structural modeling suggested that both epitopes are exposed on the surface of E2. Based on this, the identified epitopes represent a potential target for virus neutralization and might be involved in the early steps of CSFV infection. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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18 pages, 3320 KiB

Open AccessArticle

Positively Charged Amino Acids in the Pestiviral E^rns Control Cell Entry, Endoribonuclease Activity and Innate Immune Evasion

by Carmela Lussi, Elena de Martin and Matthias Schweizer

Viruses 2021, 13(8), 1581; https://doi.org/10.3390/v13081581 - 10 Aug 2021

Cited by 5 | Viewed by 2628

Abstract

The genus Pestivirus, family Flaviviridae, includes four economically important viruses of livestock, i.e., bovine viral diarrhea virus-1 (BVDV-1) and -2 (BVDV-2), border disease virus (BDV) and classical swine fever virus (CSFV). E^rns and N^pro, both expressed uniquely by [...] Read more.

The genus Pestivirus, family Flaviviridae, includes four economically important viruses of livestock, i.e., bovine viral diarrhea virus-1 (BVDV-1) and -2 (BVDV-2), border disease virus (BDV) and classical swine fever virus (CSFV). E^rns and N^pro, both expressed uniquely by pestiviruses, counteract the host’s innate immune defense by interfering with the induction of interferon (IFN) synthesis. The structural envelope protein E^rns also exists in a soluble form and, by its endoribonuclease activity, degrades immunostimulatory RNA prior to their activation of pattern recognition receptors. Here, we show that at least three out of four positively-charged residues in the C-terminal glycosaminoglycan (GAG)-binding site of BVDV-E^rns are required for efficient cell entry, and that a positively charged region more upstream is not involved in cell entry but rather in RNA-binding. Moreover, the C-terminal domain on its own determines intracellular targeting, as GFP fused to the C-terminal amino acids of E^rns was found at the same compartments as wt E^rns. In summary, RNase activity and uptake into cells are both required for E^rns to act as an IFN antagonist, and the C-terminal amphipathic helix containing the GAG-binding site determines the efficiency of cell entry and its intracellular localization. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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12 pages, 805 KiB

Open AccessArticle

Proposed Update to the Taxonomy of Pestiviruses: Eight Additional Species within the Genus Pestivirus, Family Flaviviridae

by Alexander Postel, Donald B. Smith and Paul Becher

Viruses 2021, 13(8), 1542; https://doi.org/10.3390/v13081542 - 4 Aug 2021

Cited by 34 | Viewed by 3365

Abstract

Pestiviruses are plus-stranded RNA viruses belonging to the family Flaviviridae. They comprise several important pathogens like classical swine fever virus and bovine viral diarrhea virus that induce economically important animal diseases. In 2017, the last update of pestivirus taxonomy resulted in demarcation of [...] Read more.

Pestiviruses are plus-stranded RNA viruses belonging to the family Flaviviridae. They comprise several important pathogens like classical swine fever virus and bovine viral diarrhea virus that induce economically important animal diseases. In 2017, the last update of pestivirus taxonomy resulted in demarcation of 11 species designated Pestivirus A through Pestivirus K. Since then, multiple new pestiviruses have been reported including pathogens associated with disease in pigs or small ruminants. In addition, pestivirus sequences have been found during metagenomics analysis of different non-ungulate hosts (bats, rodents, whale, and pangolin), but the consequences of this pestivirus diversity for animal health still need to be established. To provide a systematic classification of the newly discovered viruses, we analyzed the genetic relationship based on complete coding sequences (cds) and deduced polyprotein sequences and calculated pairwise distances that allow species demarcation. In addition, phylogenetic analysis was performed based on a highly conserved region within the non-structural protein NS5B. Taking into account the genetic relationships observed together with available information about antigenic properties, host origin, and characteristics of disease, we propose to expand the number of pestivirus species to 19 by adding eight additional species designated Pestivirus L through Pestivirus S. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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17 pages, 1511 KiB

Open AccessArticle

Comparative Analysis of Tunisian Sheep-like Virus, Bungowannah Virus and Border Disease Virus Infection in the Porcine Host

by Denise Meyer, Alexander Postel, Anastasia Wiedemann, Gökce Nur Cagatay, Sara Ciulli, Annalisa Guercio and Paul Becher

Viruses 2021, 13(8), 1539; https://doi.org/10.3390/v13081539 - 4 Aug 2021

Cited by 5 | Viewed by 2402

Abstract

Apart from the established pestivirus species Pestivirus A to Pestivirus K novel species emerged. Pigs represent not only hosts for porcine pestiviruses, but are also susceptible to bovine viral diarrhea virus, border disease virus (BDV) and other ruminant pestiviruses. The present study focused [...] Read more.

Apart from the established pestivirus species Pestivirus A to Pestivirus K novel species emerged. Pigs represent not only hosts for porcine pestiviruses, but are also susceptible to bovine viral diarrhea virus, border disease virus (BDV) and other ruminant pestiviruses. The present study focused on the characterization of the ovine Tunisian sheep-like virus (TSV) as well as Bungowannah virus (BuPV) and BDV strain Frijters, which were isolated from pigs. For this purpose, we performed genetic characterization based on complete coding sequences, studies on virus replication in cell culture and in domestic pigs, and cross-neutralization assays using experimentally derived sera. TSV forms a distinct phylogenetic group more closely related to Pestivirus C (classical swine fever virus, CSFV) than to Pestivirus D (BDV). In contrast to BDV and BuPV, TSV replicates by far more efficiently on ovine than on porcine cells. Nevertheless, pigs were susceptible to TSV. As a consequence of close antigenic relatedness of TSV to CSFV, cross-reactivity was detected in CSFV-specific antibody assays. In conclusion, TSV is genetically closely related to CSFV and can replicate in domestic pigs. Due to close antigenic relatedness, field infections of pigs with TSV and other ruminant pestiviruses can interfere with serological diagnosis of classical swine fever. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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20 pages, 4462 KiB

Open AccessArticle

Characterization of a Cytopathogenic Reporter CSFV

by Carina Maria Reuscher, Lisa Schmidt, Anette Netsch and Benjamin Lamp

Viruses 2021, 13(7), 1209; https://doi.org/10.3390/v13071209 - 23 Jun 2021

Cited by 3 | Viewed by 2818

Abstract

Cytopathogenic (cp) pestiviruses frequently emerge in cattle that are persistently infected with the bovine viral diarrhea virus (BVDV) as a consequence of RNA recombination and mutation. They induce apoptosis in infected tissue cultures, are highly attenuated in the immunocompetent host, and unable to [...] Read more.

Cytopathogenic (cp) pestiviruses frequently emerge in cattle that are persistently infected with the bovine viral diarrhea virus (BVDV) as a consequence of RNA recombination and mutation. They induce apoptosis in infected tissue cultures, are highly attenuated in the immunocompetent host, and unable to establish persistent infections after diaplacental infections. Cp strains of BVDV have been used as naturally attenuated live vaccines and for species-specific plaque reduction tests for the indirect serological detection of BVDV. Here, we present a genetically engineered cp strain of the classical swine fever virus (CSFV). Cytopathogenicity of the strain was induced by the insertion of ubiquitin embedded in a large NS3 to NS4B duplication. The CSFV RNA genome was stabilized by the inactivation of the NS2 autoprotease, hindering the deletion of the insertion and the reversion to a wild-type genome. Additional insertion of a mCherry gene at the 5′-end of the E2 gene allowed fluorescence-verified plaque reduction assays for CSFV, thus providing a novel, cost-efficient diagnostic tool. This genetically stabilized cp CSFV strain could be further used as a basis for potential new modified live vaccines. Taken together, we applied reverse genetics to rationally fixate a typical cp NS3 duplication in a CSFV genome. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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38 pages, 8082 KiB

Open AccessArticle

The E^rns Carboxyterminus: Much More Than a Membrane Anchor

by Birke Andrea Tews, Anne Klingebeil, Juliane Kühn, Kati Franzke, Till Rümenapf and Gregor Meyers

Viruses 2021, 13(7), 1203; https://doi.org/10.3390/v13071203 - 23 Jun 2021

Cited by 4 | Viewed by 2794

Abstract

Pestiviruses express the unique essential envelope protein E^rns, which exhibits RNase activity, is attached to membranes by a long amphipathic helix, and is partially secreted from infected cells. The RNase activity of E^rns is directly connected with pestivirus virulence. Formation [...] Read more.

Pestiviruses express the unique essential envelope protein E^rns, which exhibits RNase activity, is attached to membranes by a long amphipathic helix, and is partially secreted from infected cells. The RNase activity of E^rns is directly connected with pestivirus virulence. Formation of homodimers and secretion of the protein are hypothesized to be important for its role as a virulence factor, which impairs the host’s innate immune response to pestivirus infection. The unusual membrane anchor of E^rns raises questions with regard to proteolytic processing of the viral polyprotein at the E^rns carboxy-terminus. Moreover, the membrane anchor is crucial for establishing the critical equilibrium between retention and secretion and ensures intracellular accumulation of the protein at the site of virus budding so that it is available to serve both as structural component of the virion and factor controlling host immune reactions. In the present manuscript, we summarize published as well as new data on the molecular features of E^rns including aspects of its interplay with the other two envelope proteins with a special focus on the biochemistry of the E^rns membrane anchor. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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13 pages, 4312 KiB

Open AccessArticle

A β-Hairpin Motif in the Envelope Protein E2 Mediates Receptor Binding of Bovine Viral Diarrhea Virus

by Fernando Merwaiss, María José Pascual, María Trinidad Pomilio, María Gabriela Lopez, Oscar A. Taboga and Diego E. Alvarez

Viruses 2021, 13(6), 1157; https://doi.org/10.3390/v13061157 - 17 Jun 2021

Cited by 5 | Viewed by 2478

Abstract

Pestivirus envelope protein E2 is crucial to virus infection and accomplishes virus-receptor interaction during entry. However, mapping of E2 residues mediating these interactions has remained unexplored. In this study, to investigate the structure-function relationship for a β-hairpin motif exposed to the solvent in [...] Read more.

Pestivirus envelope protein E2 is crucial to virus infection and accomplishes virus-receptor interaction during entry. However, mapping of E2 residues mediating these interactions has remained unexplored. In this study, to investigate the structure-function relationship for a β-hairpin motif exposed to the solvent in the crystal structure of bovine viral diarrhea virus (BVDV) E2, we designed two amino acidic substitutions that result in a change of electrostatic potential. First, using wild type and mutant E2 expressed as soluble recombinant proteins, we found that the mutant protein had reduced binding to susceptible cells compared to wild type and diminished ability to inhibit BVDV infection, suggesting a lower affinity for BVDV receptors. We then analyzed the effect of β-hairpin mutations in the context of recombinant viral particles. Mutant viruses recovered from cell culture supernatant after transfection of recombinant RNA had almost completely inhibited ability to re-infect susceptible cells, indicating an impact of mutations on BVDV infectivity. Finally, sequential passaging of the mutant virus resulted in the selection of a viral population in which β-hairpin mutations reverted to the wild type sequence to restore infectivity. Taken together, our results show that this conserved region of the E2 protein is critical for the interaction with host cell receptors. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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15 pages, 2163 KiB

Open AccessArticle

Prevalence of Linda Virus Neutralizing Antibodies in the Austrian Pig Population

by Alexandra Kiesler, Jakob Plankensteiner, Lukas Schwarz, Christiane Riedel, Kerstin Seitz, Marlene Mötz, Andrea Ladinig, Benjamin Lamp and Till Rümenapf

Viruses 2021, 13(6), 1001; https://doi.org/10.3390/v13061001 - 27 May 2021

Cited by 7 | Viewed by 2929

Abstract

A novel pestivirus species, termed Lateral-shaking Inducing Neuro-Degenerative Agent virus (LindaV), was discovered in a piglet-producing farm in Austria in 2015 related to severe congenital tremor cases. Since the initial outbreak LindaV has not been found anywhere else. In this study, we determined [...] Read more.

A novel pestivirus species, termed Lateral-shaking Inducing Neuro-Degenerative Agent virus (LindaV), was discovered in a piglet-producing farm in Austria in 2015 related to severe congenital tremor cases. Since the initial outbreak LindaV has not been found anywhere else. In this study, we determined the seroprevalence of LindaV infections in the domestic pig population of Austria. A fluorophore labeled infectious cDNA clone of LindaV (mCherry-LindaV) was generated and used in serum virus neutralization (SVN) assays for the detection of LindaV specific neutralizing antibodies in porcine serum samples. In total, 637 sera from sows and gilts from five federal states of Austria, collected between the years 2015 and 2020, were analyzed. We identified a single serum showing a high neutralizing antibody titer, that originated from a farm (Farm S2) in the proximity of the initially affected farm. The analysis of 57 additional sera from Farm S2 revealed a wider spread of LindaV in this pig herd. Furthermore, a second LindaV strain originating from this farm could be isolated in cell culture and was further characterized at the genetic level. Possible transmission routes and virus reservoir hosts of this emerging porcine virus need to be addressed in future studies. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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7 pages, 476 KiB

Open AccessArticle

Detection of Atypical Porcine Pestivirus in Piglets from Danish Sow Herds

by Kasper Pedersen, Charlotte Sonne Kristensen, Bertel Strandbygaard, Anette Bøtner and Thomas Bruun Rasmussen

Viruses 2021, 13(5), 717; https://doi.org/10.3390/v13050717 - 21 Apr 2021

Cited by 7 | Viewed by 2395

Abstract

Atypical porcine pestivirus (APPV) was first discovered in North America in 2015 and was later shown to be associated with congenital tremor (CT) in piglets. CT is an occasional challenge in some Danish sow herds. Therefore, we initiated an observational case control study [...] Read more.

Atypical porcine pestivirus (APPV) was first discovered in North America in 2015 and was later shown to be associated with congenital tremor (CT) in piglets. CT is an occasional challenge in some Danish sow herds. Therefore, we initiated an observational case control study to clarify a possible relationship between CT and APPV in Danish pig production. Blood samples were collected from piglets affected by CT (n = 55) in ten different sow herds and from healthy piglets in five sow herds without a history of CT piglets (n = 25), as well as one sow herd with a sporadic occurrence of CT (n = 5). APPV was detected by RT-qPCR in all samples from piglets affected by CT and in three out of five samples from piglets in the herd with a sporadic occurrence of CT. In the herds without a history of CT, only one out of 25 piglets were positive for APPV. In addition, farmers or veterinarians in CT-affected herds were asked about their experience of the issue. CT is most often seen in gilt litters, and a substantial increase in pre-weaning mortality is only observed in severe cases. According to our investigations, APPV is a common finding in piglets suffering from CT in Denmark. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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15 pages, 2291 KiB

Open AccessArticle

Efficacy of Oral Vaccine against Classical Swine Fever in Wild Boar and Estimation of the Disease Dynamics in the Quantitative Approach

by Enkhbold Bazarragchaa, Norikazu Isoda, Taksoo Kim, Madoka Tetsuo, Satoshi Ito, Keita Matsuno and Yoshihiro Sakoda

Viruses 2021, 13(2), 319; https://doi.org/10.3390/v13020319 - 20 Feb 2021

Cited by 9 | Viewed by 3665

Abstract

Classical swine fever virus (CSFV) in the wild boar population has been spreading in Japan, alongside outbreaks on pigs, since classical swine fever (CSF) reemerged in September 2018. The vaccination using oral bait vaccine was initially implemented in Gifu prefecture in March 2019. [...] Read more.

Classical swine fever virus (CSFV) in the wild boar population has been spreading in Japan, alongside outbreaks on pigs, since classical swine fever (CSF) reemerged in September 2018. The vaccination using oral bait vaccine was initially implemented in Gifu prefecture in March 2019. In the present study, antibodies against CSFV in wild boar were assessed in 1443 captured and dead wild boars in Gifu prefecture. After the implementation of oral vaccination, the increase of the proportion of seropositive animals and their titer in wild boars were confirmed. Quantitative analysis of antigen and antibodies against CSFV in wild boar implies potential disease diversity in the wild boar population. Animals with status in high virus replication (Ct < 30) and non- or low-immune response were confirmed and were sustained at a certain level after initial oral vaccination. Through continuous vaccination periods, the increase of seroprevalence among wild boar and the decrease of CSFV-positive animals were observed. The epidemiological analysis based on the quantitative virological outcomes could provide more information on the efficacy of oral vaccination and dynamics of CSF in the wild boar population, which will help to improve the implementation of control measures for CSF in countries such as Japan and neighboring countries. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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Review

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16 pages, 5203 KiB

Open AccessReview

Atypical Porcine Pestiviruses: Relationships and Conserved Structural Features

by Christiane Riedel, Hazel Aitkenhead, Kamel El Omari and Till Rümenapf

Viruses 2021, 13(5), 760; https://doi.org/10.3390/v13050760 - 26 Apr 2021

Cited by 6 | Viewed by 3354

Abstract

For two decades, the genus pestivirus has been expanding and the host range now extends to rodents, bats and marine mammals. In this review, we focus on one of the most diverse pestiviruses, atypical porcine pestivirus or pestivirus K, comparing its special traits [...] Read more.

For two decades, the genus pestivirus has been expanding and the host range now extends to rodents, bats and marine mammals. In this review, we focus on one of the most diverse pestiviruses, atypical porcine pestivirus or pestivirus K, comparing its special traits to what is already known at the structural and functional level from other pestiviruses. Full article

(This article belongs to the Special Issue Advances in Pestivirus Research)

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