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Pseudorabies Virus Infections

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A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 52040

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Special Issue Editor

Dr. Barbara Klupp

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Guest Editor

Laboratory Head, Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
Interests: pseudorabies virus; herpes virus; virus entry; membrane fusion; viral glycoproteins; nuclear egress; herpesvirus-host cell interaction

Special Issue Information

Dear Colleagues,

Pseudorabies virus (PrV), with its correct taxonomic name Suid alphaherpesvirus 1 is the causative agent of Aujeszky´s Disease, an infection with severe economic impact for pig producers. Members of the Suidae family are the only species, which can survive an infection. However, nearly all mammals excluding humans and other higher primates are susceptible. In these species, infection is always lethal and characterized by severe “rabies-like” central nervous symptoms and extensive pruritus, which resulted in the names “pseudorabies” and “mad itch”. The recent severe outbreaks of Aujeszky’s Disease in China, despite intensive vaccination, highlight the importance of continuing research.

PrV is a typical member of the Alphaherpesvirinae subfamily and shares numerous features with e.g. the human pathogens herpes simplex virus 1 and 2 including similar genome organization and comparable protein content. Despite these similarities, PrV differs by its broad host spectrum in vitro and in vivo. Host range, short replication cycle, pronounced neurotropism, the availability of its natural host for infection experiments and apathogenicity for humans render PrV a perfect model to study not only herpesvirus replication in detail but also virus-host interactions. Within the last two decades, an enormous amount of data on the molecular basis of PrV replication in vitro and in vivo has been obtained.

For this special Issue of Pathogens, we invite you to submit either an original research article or a review summarizing different facets of pseudorabies virus infection. Manuscripts highlighting the common aspects and differences in PrV replication, basic mechanisms of herpesvirus infection in vitro and in vivo, its interaction with the host immune system, the widespread application as tracer for identification of neuronal networks, the use as vectored vaccine, and the molecular basis for the massive outbreaks of disease are very welcome. We look forward to your contribution.

Dr. Barbara Klupp
Guest Editor

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Keywords

Pseudorabies virus
Animal herpesviruses
Molecular biology
Virus-host cell interaction
Viral replication
Viral gene expression
Latency and reactivation
Evasion of innate immunity
Neuronal tracer
Vectored vaccine

Published Papers (12 papers)

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Editorial

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2 pages, 145 KiB

Open AccessEditorial

Pseudorabies Virus Infections

by Barbara G. Klupp

Pathogens 2021, 10(6), 719; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10060719 - 08 Jun 2021

Cited by 6 | Viewed by 2118

Abstract

Suid alphaherpesvirus 1 (SuHV-1), better known as Pseudorabies virus (PrV), an alphaherpesvirus of swine, is the causative agent of Aujeszky’s Disease [...] Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

Research

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21 pages, 2860 KiB

Open AccessArticle

An Integrated Sequencing Approach for Updating the Pseudorabies Virus Transcriptome

by Gábor Torma, Dóra Tombácz, Zsolt Csabai, Dániel Göbhardter, Zoltán Deim, Michael Snyder and Zsolt Boldogkői

Pathogens 2021, 10(2), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10020242 - 20 Feb 2021

Cited by 8 | Viewed by 5281

Abstract

In the last couple of years, the implementation of long-read sequencing (LRS) technologies for transcriptome profiling has uncovered an extreme complexity of viral gene expression. In this study, we carried out a systematic analysis on the pseudorabies virus transcriptome by combining our current data obtained by using Pacific Biosciences Sequel and Oxford Nanopore Technologies MinION sequencing with our earlier data generated by other LRS and short-read sequencing techniques. As a result, we identified a number of novel genes, transcripts, and transcript isoforms, including splice and length variants, and also confirmed earlier annotated RNA molecules. One of the major findings of this study is the discovery of a large number of 5′-truncations of larger putative mRNAs being 3′-co-terminal with canonical mRNAs of PRV. A large fraction of these putative RNAs contain in-frame ATGs, which might initiate translation of N-terminally truncated polypeptides. Our analyses indicate that CTO-S, a replication origin-associated RNA molecule is expressed at an extremely high level. This study demonstrates that the PRV transcriptome is much more complex than previously appreciated. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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15 pages, 6049 KiB

Open AccessArticle

Influence of N-glycosylation on Expression and Function of Pseudorabies Virus Glycoprotein gB

by Melina Vallbracht, Barbara G. Klupp and Thomas C. Mettenleiter

Pathogens 2021, 10(1), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens10010061 - 12 Jan 2021

Cited by 6 | Viewed by 2530

Abstract

Envelope glycoprotein (g)B is conserved throughout the Herpesviridae and mediates fusion of the viral envelope with cellular membranes for infectious entry and spread. Like all viral envelope fusion proteins, gB is modified by asparagine (N)-linked glycosylation. Glycans can contribute to protein function, intracellular transport, trafficking, structure and immune evasion. gB of the alphaherpesvirus pseudorabies virus (PrV) contains six consensus sites for N-linked glycosylation, but their functional relevance is unknown. Here, we investigated the occupancy and functional relevance of N-glycosylation sites in PrV gB. To this end, all predicted N-glycosylation sites were inactivated either singly or in combination by the introduction of conservative mutations (N➔Q). The resulting proteins were tested for expression, fusion activity in cell–cell fusion assays and complementation of a gB-deficient PrV mutant. Our results indicate that all six sites are indeed modified. However, while glycosylation at most sites was dispensable for gB expression and fusogenicity, inactivation of N154 and N700 affected gB processing by furin cleavage and surface localization. Although all single mutants were functional in cell–cell fusion and viral entry, simultaneous inactivation of all six N-glycosylation sites severely impaired fusion activity and viral entry, suggesting a critical role of N-glycans for maintaining gB structure and function. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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13 pages, 968 KiB

Open AccessArticle

An Unbiased Approach to Mapping the Signaling Network of the Pseudorabies Virus US3 Protein

by Robert J. J. Jansens, Sandra Marmiroli and Herman W. Favoreel

Pathogens 2020, 9(11), 916; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9110916 - 05 Nov 2020

Cited by 5 | Viewed by 2323

Abstract

The US3 serine/threonine protein kinase is conserved among the alphaherpesvirus family and represents an important virulence factor. US3 plays a role in viral nuclear egress, induces dramatic alterations of the cytoskeleton, represses apoptosis, enhances gene expression and modulates the immune response. Although several substrates of US3 have been identified, an unbiased screen to identify US3 phosphorylation targets has not yet been described. Here, we perform a shotgun and phosphoproteomics analysis of cells expressing the US3 protein of pseudorabies virus (PRV) to identify US3 phosphorylation targets in an unbiased way. We identified several cellular proteins that are differentially phosphorylated upon US3 expression and validated the phosphorylation of lamin A/C at serine 404, both in US3-transfected and PRV-infected cells. These results provide new insights into the signaling network of the US3 protein kinase and may serve as a basis for future research into the role of the US3 protein in the viral replication cycle. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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15 pages, 3657 KiB

Open AccessArticle

Monitoring of Pseudorabies in Wild Boar of Germany—A Spatiotemporal Analysis

by Nicolai Denzin, Franz J. Conraths, Thomas C. Mettenleiter, Conrad M. Freuling and Thomas Müller

Pathogens 2020, 9(4), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9040276 - 10 Apr 2020

Cited by 11 | Viewed by 2518

Abstract

To evaluate recent developments regarding the epidemiological situation of pseudorabies virus (PRV) infections in wild boar populations in Germany, nationwide serological monitoring was conducted between 2010 and 2015. During this period, a total of 108,748 sera from wild boars were tested for the presence of PRV-specific antibodies using commercial enzyme-linked immunosorbent assays. The overall PRV seroprevalence was estimated at 12.09% for Germany. A significant increase in seroprevalence was observed in recent years indicating both a further spatial spread and strong disease dynamics. For spatiotemporal analysis, data from 1985 to 2009 from previous studies were incorporated. The analysis revealed that PRV infections in wild boar were endemic in all German federal states; the affected area covers at least 48.5% of the German territory. There were marked differences in seroprevalence at district levels as well as in the relative risk (RR) of infection of wild boar throughout Germany. We identified several smaller clusters and one large region, where the RR was two to four times higher as compared to the remaining areas under investigation. Based on the present monitoring intensity and outcome, we provide recommendations with respect to future monitoring efforts concerning PRV infections in wild boar in Germany. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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12 pages, 1066 KiB

Open AccessEditor’s ChoiceArticle

Genetic Diversity among Pseudorabies Viruses Isolated from Dogs in France from 2006 to 2018

by Céline Deblanc, Aurélie Oger, Gaëlle Simon and Marie-Frédérique Le Potier

Pathogens 2019, 8(4), 266; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens8040266 - 26 Nov 2019

Cited by 14 | Viewed by 2798

Abstract

Pseudorabies (PR), also known as Aujeszky’s disease, is an economically important disease for the pig industry. It has been eradicated in domestic pigs in many European countries, including France, but its causative agent—Suid Herpesvirus 1—is still circulating in wild boars. The risk of endemic PR in wild fauna lies in reintroducing the virus among domestic pigs and transmitting it to other mammals, especially hunting dogs for which the disease is rapidly fatal. As such infections are regularly reported in France, this study genetically characterized canine PR virus strains in the country to obtain information on their diversity and evolution. Partial sequencing of the glycoprotein C-encoding gene from 55 virus strains isolated from dogs between 2006 and 2018 showed that 14 strains belonged to genotype I-clade A and another 38 to genotype I-clade B, two clades usually reported in Western Europe. More surprisingly, three strains were found to belong to genotype II, suggesting an Asian origin. Genotype I-clade A strains exhibited the highest diversity as five geographically segregated genogroups were identified. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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14 pages, 3594 KiB

Open AccessArticle

Antiviral Activity of Germacrone against Pseudorabies Virus in Vitro

by Wanting He, Xiaofeng Zhai, Jingyin Su, Rui Ye, Yuna Zheng and Shuo Su

Pathogens 2019, 8(4), 258; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens8040258 - 22 Nov 2019

Cited by 25 | Viewed by 3497

Abstract

Pseudorabies virus (PRV), a member of the Herpesviridae, is the causative agent of an acute infectious disease in a variety of animals. The emergence of a novel variant strain brought huge economic losses to the pig industry since classical vaccine strains were not completely effective against variant strains. Therefore, the development of new anti-pseudorabies virus drugs and vaccines is of great significance for the treatment and prevention of pseudorabies. In this study, we found that germacrone, one of the major components of the essential oils extracted from Rhizoma Curcuma, was able to effectively inhibit PRV replication in a dose-dependent manner in vitro. Germacrone showed antiviral activity against PRV in the early phase of the viral replication cycle. Moreover, we found that germacrone does not directly kill the virus, nor does it affect the expression of the PRV receptor protein nectin-1, nectin-2, and CD155. Our results suggest germacrone could be used as an efficient microbicide or immunomodulatory agent in the control of the emerging variant PRV. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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Review

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13 pages, 2293 KiB

Open AccessEditor’s ChoiceReview

The Attenuated Pseudorabies Virus Vaccine Strain Bartha K61: A Brief Review on the Knowledge Gathered during 60 Years of Research

by Jonas L. Delva, Hans J. Nauwynck, Thomas C. Mettenleiter and Herman W. Favoreel

Pathogens 2020, 9(11), 897; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9110897 - 27 Oct 2020

Cited by 38 | Viewed by 3698

Abstract

Pseudorabies virus (PRV) is a member of the alphaherpesvirus subfamily of the herpesviruses and is the causative agent of Aujeszky’s disease in pigs, causing respiratory, neurological, and reproductive symptoms. Given the heavy economic losses associated with Aujeszky’s disease epidemics, great efforts were made to develop efficacious vaccines. One of the best modified live vaccines to this day is the attenuated Bartha K61 strain. The use of this vaccine in extensive vaccination programs worldwide has assisted considerably in the eradication of PRV from the domesticated pig population in numerous countries. The Bartha K61 strain was described in 1961 by Adorján Bartha in Budapest and was obtained by serial passaging in different cell cultures. Ever since, it has been intensively studied by several research groups, for example, to explore its efficacy as a vaccine strain, to molecularly and mechanistically explain its attenuation, and to use it as a retrograde neuronal tracer and as a vector vaccine. Given that the Bartha K61 vaccine strain celebrates its 60th birthday in 2021 with no sign of retirement, this review provides a short summary of the knowledge on its origin, characteristics, and use as a molecular tool and as a vaccine. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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23 pages, 10380 KiB

Open AccessEditor’s ChoiceReview

Comparative Pathology of Pseudorabies in Different Naturally and Experimentally Infected Species—A Review

by Julia Sehl and Jens Peter Teifke

Pathogens 2020, 9(8), 633; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9080633 - 04 Aug 2020

Cited by 39 | Viewed by 10616

Abstract

The pseudorabies virus (PRV) is an alphaherpesvirus and the causative agent of Aujeszky’s disease (AD). PRV infects a wide range of animal species including swine as the natural host as well as ruminants, carnivores, rodents and lagomorphs. In these species, except for the pig, PRV infection causes acute, severe disease, characterized by insatiable itching, and is always lethal. Horses, chickens and non-human primates have been shown to be largely resistant to PRV infection, while disease in humans is still controversial. PRV is a pantropic virus, which preferably invades neural tissue, but also infects epithelia of various organs, whereupon multisystemic lesions may result. Although AD is mainly associated with severe pruritus, also known as “mad itch”, there are notable differences regarding infection route, clinical signs, viral distribution and lesion patterns in different animal species. In this comprehensive review, we will present clinico-pathologic findings from different species, which have been either shown to be susceptible to PRV infection or have been tested experimentally. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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7 pages, 1978 KiB

Open AccessReview

Aujeszky’s Disease and the Development of the Marker/DIVA Vaccination Concept

by Thomas C. Mettenleiter

Pathogens 2020, 9(7), 563; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9070563 - 12 Jul 2020

Cited by 28 | Viewed by 3994

Abstract

Aujeszky’s disease or pseudorabies is an infection of animals caused by Suid alphaherpesvirus 1, also designated as pseudorabies virus (PrV). Whereas many mammals are susceptible to PrV, only pigs are able to survive productive infection. Early reports on this disease originate from cattle and companion animals with the hallmark sign of “mad itch”, meaning development of pruritus. Although first reports date back to the early 19th century, it was Aladár Aujeszky who in 1902 described this disease, which has since been named after him, as a separate entity. AD expanded in the 20th century, despite efforts to control this infection in the growing pig farming industry. Live-attenuated vaccines were developed in the early 1960s, which assisted early eradication efforts. A major breakthrough in animal vaccinology occurred in the mid-1980s, when it was found that several live-attenuated PrV vaccine strains lacked a significant portion of the genome, including the gene encoding a major immunogenic viral envelope glycoprotein. Upon the development of a suitable serological assay, the first marker vaccine/DIVA concept (differentiating infected from vaccinated animals) was developed. Moreover, the first genetically modified live vaccines emanated from molecular work on PrV. Thus, AD serves as a hallmark for the history of veterinary virology as well as for pioneering novel strategies for controlling animal infectious diseases. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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28 pages, 1972 KiB

Open AccessEditor’s ChoiceReview

The Neuropathic Itch Caused by Pseudorabies Virus

by Kathlyn Laval and Lynn W. Enquist

Pathogens 2020, 9(4), 254; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9040254 - 31 Mar 2020

Cited by 52 | Viewed by 8255

Abstract

Pseudorabies virus (PRV) is an alphaherpesvirus related to varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1). PRV is the causative agent of Aujeskzy’s disease in swine. PRV infects mucosal epithelium and the peripheral nervous system (PNS) of its host where it can establish a quiescent, latent infection. While the natural host of PRV is the swine, a broad spectrum of mammals, including rodents, cats, dogs, and cattle can be infected. Since the nineteenth century, PRV infection is known to cause a severe acute neuropathy, the so called “mad itch” in non-natural hosts, but surprisingly not in swine. In the past, most scientific efforts have been directed to eradicating PRV from pig farms by the use of effective marker vaccines, but little attention has been given to the processes leading to the mad itch. The main objective of this review is to provide state-of-the-art information on the mechanisms governing PRV-induced neuropathic itch in non-natural hosts. We highlight similarities and key differences in the pathogenesis of PRV infections between non-natural hosts and pigs that might explain their distinctive clinical outcomes. Current knowledge on the neurobiology and possible explanations for the unstoppable itch experienced by PRV-infected animals is also reviewed. We summarize recent findings concerning PRV-induced neuroinflammatory responses in mice and address the relevance of this animal model to study other alphaherpesvirus-induced neuropathies, such as those observed for VZV infection. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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Other

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15 pages, 3981 KiB

Open AccessCase Report

First Report of a Severe Outbreak of Aujeszky’s Disease in Cattle in Sicily (Italy)

by Flavia Pruiti Ciarello, Maria Teresa Capucchio, Dorotea Ippolito, Elena Colombino, Lucia Rita Maria Gibelli, Michele Fiasconaro, Ana Maria Moreno Martin and Vincenzo Di Marco Lo Presti

Pathogens 2020, 9(11), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens9110954 - 17 Nov 2020

Cited by 9 | Viewed by 3017

Abstract

Aujeszky’s disease in cattle is caused by Suid herpes virus 1. The natural infection has been reported worldwide in bovine species and it is related to direct and indirect contact with infected pigs, which represent the main reservoir of the virus. Here, it is reported the first documented outbreak of Aujeszky’s disease in cattle in Sicily (Italy). Severe itching and nonspecific neurological symptoms were the main reported clinical signs. No characteristic gross and histological features were reported other than cutaneous lesions caused by excessive pruritus and hyperaemia, haemorrhages and inflammation in the central nervous system. Diagnosis was confirmed by real time PCR and immunohistochemistry on the nervous tissue. The route of infection remained unknown, but serological data observed in pigs living in close cohabitation with cattle revealed a circulation of a wild strain of the virus in the area. This study contributes to a better knowledge of this disease in a non-conventional host and suggests the need to increase the prophylaxis control plans in specific breeding contexts. Full article

(This article belongs to the Special Issue Pseudorabies Virus Infections)

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