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Volume 11
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Viruses, Volume 11, Issue 2 (February 2019) – 107 articles

Cover Story (view full-size image): Many enveloped viruses employ late domains such as PPXY to recruit the host ESCRT machinery needed for budding and particle release. Paramyxoviruses typically lack late domain sequences, yet budding of these viruses is often ESCRT-dependent. Here, we provide evidence for a model in which paramyxoviruses use AMOTL1 as a linker to indirectly recruit the same WW domain-containing NEDD4 ubiquitin ligases for budding that other enveloped viruses recruit directly through PPXY late domains. View this paper.
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14 pages, 3302 KiB  
Review
Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors
by Kyeong-Ok Chang, Yunjeong Kim, Scott Lovell, Athri D. Rathnayake and William C. Groutas
Viruses 2019, 11(2), 197; https://doi.org/10.3390/v11020197 - 25 Feb 2019
Cited by 48 | Viewed by 10195
Abstract
Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense [...] Read more.
Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors. Full article
(This article belongs to the Special Issue Noroviruses)
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16 pages, 6722 KiB  
Article
Duck Plague Virus Promotes DEF Cell Apoptosis by Activating Caspases, Increasing Intracellular ROS Levels and Inducing Cell Cycle S-Phase Arrest
by Chuankuo Zhao, Mingshu Wang, Anchun Cheng, Qiao Yang, Ying Wu, Renyong Jia, Dekang Zhu, Shun Chen, Mafeng Liu, Xinxin Zhao, Shaqiu Zhang, Yunya Liu, Yanling Yu, Ling Zhang, Bin Tian, Mujeeb Ur Rehman, Leichang Pan and Xiaoyue Chen
Viruses 2019, 11(2), 196; https://doi.org/10.3390/v11020196 - 24 Feb 2019
Cited by 14 | Viewed by 5039
Abstract
Background: Duck plague virus (DPV) can induce apoptosis in duck embryo fibroblasts (DEFs) and in infected ducks, but the molecular mechanism of DPV-induced apoptosis remains unknown. Methods: We first used qRT-PCR and a Caspase-Glo assay to determine whether the caspase protein family plays [...] Read more.
Background: Duck plague virus (DPV) can induce apoptosis in duck embryo fibroblasts (DEFs) and in infected ducks, but the molecular mechanism of DPV-induced apoptosis remains unknown. Methods: We first used qRT-PCR and a Caspase-Glo assay to determine whether the caspase protein family plays an important role in DPV-induced apoptosis. Then, we used an intracellular ROS detection kit and the mitochondrial probe JC-1 to respectively detect ROS levels and mitochondrial membrane potential (MMP). Finally, flow cytometry was used to detect apoptosis and cell cycle progression. Results: In this study, the mRNA levels and enzymatic activities of caspase-3, caspase-7, caspase-8, and caspase-9 were significantly increased during DPV-induced apoptosis. The caspase inhibitors Z-DEVD-FMK, Z-LEHD-FMK, and Q-VD-Oph could inhibit DPV-induced apoptosis and promote viral replication. Subsequently, a significant decrease in MMP and an increase in the intracellular ROS levels were observed. Further study showed that pretreating infected cells with NAC (a ROS scavenger) decreased the intracellular ROS levels, increased the MMP, inhibited apoptosis, and promoted viral replication. Finally, we showed that DPV infection can cause cell cycle S-phase arrest. Conclusions: This study shows that DPV causes cell cycle S-phase arrest and leads to apoptosis through caspase activation and increased intracellular ROS levels. These findings may be useful for gaining an understanding of the pathogenesis of DPV and the apoptotic pathways induced by α-herpesviruses. Full article
(This article belongs to the Section Animal Viruses)
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15 pages, 1893 KiB  
Article
Classifying the Unclassified: A Phage Classification Method
by Cynthia Maria Chibani, Anton Farr, Sandra Klama, Sascha Dietrich and Heiko Liesegang
Viruses 2019, 11(2), 195; https://doi.org/10.3390/v11020195 - 24 Feb 2019
Cited by 46 | Viewed by 10118
Abstract
This work reports the method ClassiPhage to classify phage genomes using sequence derived taxonomic features. ClassiPhage uses a set of phage specific Hidden Markov Models (HMMs) generated from clusters of related proteins. The method was validated on all publicly available genomes of phages [...] Read more.
This work reports the method ClassiPhage to classify phage genomes using sequence derived taxonomic features. ClassiPhage uses a set of phage specific Hidden Markov Models (HMMs) generated from clusters of related proteins. The method was validated on all publicly available genomes of phages that are known to infect Vibrionaceae. The phages belong to the well-described phage families of Myoviridae, Podoviridae, Siphoviridae, and Inoviridae. The achieved classification is consistent with the assignments of the International Committee on Taxonomy of Viruses (ICTV), all tested phages were assigned to the corresponding group of the ICTV-database. In addition, 44 out of 58 genomes of Vibrio phages not yet classified could be assigned to a phage family. The remaining 14 genomes may represent phages of new families or subfamilies. Comparative genomics indicates that the ability of the approach to identify and classify phages is correlated to the conserved genomic organization. ClassiPhage classifies phages exclusively based on genome sequence data and can be applied on distinct phage genomes as well as on prophage regions within host genomes. Possible applications include (a) classifying phages from assembled metagenomes; and (b) the identification and classification of integrated prophages and the splitting of phage families into subfamilies. Full article
(This article belongs to the Special Issue Diversity and Evolution of Phage Genomes)
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9 pages, 1665 KiB  
Article
Priorities, Barriers, and Facilitators towards International Guidelines for the Delivery of Supportive Clinical Care during an Ebola Outbreak: A Cross-Sectional Survey
by Marie-Claude Battista, Christine Loignon, Lynda Benhadj, Elysee Nouvet, Srinivas Murthy, Robert Fowler, Neill K. J. Adhikari, Adnan Haj-Moustafa, Alex P. Salam, Adrienne K. Chan, Sharmistha Mishra, Francois Couturier, Catherine Hudon, Peter Horby, Richard Bedell, Michael Rekart, Jan Hajek and Francois Lamontagne
Viruses 2019, 11(2), 194; https://doi.org/10.3390/v11020194 - 23 Feb 2019
Cited by 7 | Viewed by 5428
Abstract
During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus [...] Read more.
During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus Disease (EVD). We conducted a cross-sectional survey of key stakeholders involved in the response to the 2014–2016 West African EVD outbreak. Out of 57 email invitations, 44 responses were received, and 29 respondents completed the survey. The respondents listed insufficient numbers of health workers (23/29, 79%), improper tools for the documentation of clinical data (n = 22/28, 79%), insufficient material resources (n = 22/29, 76%), and unadapted personal protective equipment (n = 20/28, 71%) as the main barriers to the provision of supportive care in ETUs. Facilitators to the provision of supportive care included team camaraderie (n in agreement = 25/28, 89%), ability to speak the local language (22/28, 79%), and having treatment protocols in place (22/28, 79%). This survey highlights a consensus across various stakeholders involved in the response to the 2014–2016 EVD outbreak on a limited number of high-priority supportive care interventions for clinical practice guidelines. Identified barriers and facilitators further inform the application of guidelines. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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13 pages, 2042 KiB  
Article
In Vivo Characterization of Avian Influenza A (H5N1) and (H7N9) Viruses Isolated from Canadian Travelers
by Yao Lu, Shelby Landreth, Amit Gaba, Magda Hlasny, Guanqun Liu, Yanyun Huang and Yan Zhou
Viruses 2019, 11(2), 193; https://doi.org/10.3390/v11020193 - 23 Feb 2019
Cited by 11 | Viewed by 5524
Abstract
Highly pathogenic avian influenza (HPAI) H5N1 and low pathogenic avian influenza (LPAI) H7N9 viruses pose a severe threat to public health through zoonotic infection, causing severe respiratory disease in humans. While HPAI H5N1 human infections have typically been reported in Asian countries, avian [...] Read more.
Highly pathogenic avian influenza (HPAI) H5N1 and low pathogenic avian influenza (LPAI) H7N9 viruses pose a severe threat to public health through zoonotic infection, causing severe respiratory disease in humans. While HPAI H5N1 human infections have typically been reported in Asian countries, avian H7N9 human infections have been reported mainly in China. However, Canada reported a case of fatal human infection by the HPAI H5N1 virus in 2014, and two cases of human illness associated with avian H7N9 virus infection in 2015. While the genomes of the causative viruses A/Alberta/01/2014 (H5N1) (AB14 (H5N1)) and A/British Columbia/1/2015 (H7N9) (BC15 (H7N9)) are reported, the isolates had not been evaluated for their pathogenicity in animal models. In this study, we characterized the pathogenicity of AB14 (H5N1) and BC15 (H7N9) and found that both strain isolates are highly lethal in mice. AB14 (H5N1) caused systemic viral infection and erratic proinflammatory cytokine gene expression in different organs. In contrast, BC15 (H7N9) replicated efficiently only in the respiratory tract, and was a potent inducer for proinflammatory cytokine genes in the lungs. Our study provides experimental evidence to complement the specific human case reports and animal models for evaluating vaccine and antiviral candidates against potential influenza pandemics. Full article
(This article belongs to the Special Issue CSV2018: The 2nd symposium of the Canadian Society for Virology (CSV))
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11 pages, 1224 KiB  
Review
Immune System Modulation and Viral Persistence in Bats: Understanding Viral Spillover
by Sonu Subudhi, Noreen Rapin and Vikram Misra
Viruses 2019, 11(2), 192; https://doi.org/10.3390/v11020192 - 23 Feb 2019
Cited by 108 | Viewed by 17036
Abstract
Bats harbor a myriad of viruses and some of these viruses may have spilled over to other species including humans. Spillover events are rare and several factors must align to create the “perfect storm” that would ultimately lead to a spillover. One of [...] Read more.
Bats harbor a myriad of viruses and some of these viruses may have spilled over to other species including humans. Spillover events are rare and several factors must align to create the “perfect storm” that would ultimately lead to a spillover. One of these factors is the increased shedding of virus by bats. Several studies have indicated that bats have unique defense mechanisms that allow them to be persistently or latently infected with viruses. Factors leading to an increase in the viral load of persistently infected bats would facilitate shedding of virus. This article reviews the unique nature of bat immune defenses that regulate virus replication and the various molecular mechanisms that play a role in altering the balanced bat–virus relationship. Full article
(This article belongs to the Special Issue Viruses and Bats 2019)
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13 pages, 780 KiB  
Review
The Virioneuston: A Review on Viral–Bacterial Associations at Air–Water Interfaces
by Janina Rahlff
Viruses 2019, 11(2), 191; https://doi.org/10.3390/v11020191 - 22 Feb 2019
Cited by 17 | Viewed by 7491
Abstract
Vast biofilm-like habitats at air–water interfaces of marine and freshwater ecosystems harbor surface-dwelling microorganisms, which are commonly referred to as neuston. Viruses in the microlayer, i.e., the virioneuston, remain the most enigmatic biological entities in boundary surface layers due to their potential ecological [...] Read more.
Vast biofilm-like habitats at air–water interfaces of marine and freshwater ecosystems harbor surface-dwelling microorganisms, which are commonly referred to as neuston. Viruses in the microlayer, i.e., the virioneuston, remain the most enigmatic biological entities in boundary surface layers due to their potential ecological impact on the microbial loop and major air–water exchange processes. To provide a broad picture of the viral–bacterial dynamics in surface microlayers, this review compiles insights on the challenges that viruses likely encounter at air–water interfaces. By considering viral abundance and morphology in surface microlayers, as well as dispersal and infection mechanisms as inferred from the relevant literature, this work highlights why studying the virioneuston in addition to the bacterioneuston is a worthwhile task. In this regard, major knowledge gaps and possible future research directions are discussed. Full article
(This article belongs to the Section Bacterial Viruses)
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35 pages, 8902 KiB  
Review
Novel Approaches for The Development of Live Attenuated Influenza Vaccines
by Pilar Blanco-Lobo, Aitor Nogales, Laura Rodríguez and Luis Martínez-Sobrido
Viruses 2019, 11(2), 190; https://doi.org/10.3390/v11020190 - 22 Feb 2019
Cited by 50 | Viewed by 9822
Abstract
Influenza virus still represents a considerable threat to global public health, despite the advances in the development and wide use of influenza vaccines. Vaccination with traditional inactivate influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV) remains the main strategy in the control of [...] Read more.
Influenza virus still represents a considerable threat to global public health, despite the advances in the development and wide use of influenza vaccines. Vaccination with traditional inactivate influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV) remains the main strategy in the control of annual seasonal epidemics, but it does not offer protection against new influenza viruses with pandemic potential, those that have shifted. Moreover, the continual antigenic drift of seasonal circulating influenza viruses, causing an antigenic mismatch that requires yearly reformulation of seasonal influenza vaccines, seriously compromises vaccine efficacy. Therefore, the quick optimization of vaccine production for seasonal influenza and the development of new vaccine approaches for pandemic viruses is still a challenge for the prevention of influenza infections. Moreover, recent reports have questioned the effectiveness of the current LAIV because of limited protection, mainly against the influenza A virus (IAV) component of the vaccine. Although the reasons for the poor protection efficacy of the LAIV have not yet been elucidated, researchers are encouraged to develop new vaccination approaches that overcome the limitations that are associated with the current LAIV. The discovery and implementation of plasmid-based reverse genetics has been a key advance in the rapid generation of recombinant attenuated influenza viruses that can be used for the development of new and most effective LAIV. In this review, we provide an update regarding the progress that has been made during the last five years in the development of new LAIV and the innovative ways that are being explored as alternatives to the currently licensed LAIV. The safety, immunogenicity, and protection efficacy profile of these new LAIVs reveal their possible implementation in combating influenza infections. However, efforts by vaccine companies and government agencies will be needed for controlled testing and approving, respectively, these new vaccine methodologies for the control of influenza infections. Full article
(This article belongs to the Special Issue What’s New with Flu?)
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15 pages, 717 KiB  
Review
Viruses of Polar Aquatic Environments
by Sheree Yau and Mansha Seth-Pasricha
Viruses 2019, 11(2), 189; https://doi.org/10.3390/v11020189 - 22 Feb 2019
Cited by 34 | Viewed by 7278
Abstract
The poles constitute 14% of the Earth’s biosphere: The aquatic Arctic surrounded by land in the north, and the frozen Antarctic continent surrounded by the Southern Ocean. In spite of an extremely cold climate in addition to varied topographies, the polar aquatic regions [...] Read more.
The poles constitute 14% of the Earth’s biosphere: The aquatic Arctic surrounded by land in the north, and the frozen Antarctic continent surrounded by the Southern Ocean. In spite of an extremely cold climate in addition to varied topographies, the polar aquatic regions are teeming with microbial life. Even in sub-glacial regions, cellular life has adapted to these extreme environments where perhaps there are traces of early microbes on Earth. As grazing by macrofauna is limited in most of these polar regions, viruses are being recognized for their role as important agents of mortality, thereby influencing the biogeochemical cycling of nutrients that, in turn, impact community dynamics at seasonal and spatial scales. Here, we review the viral diversity in aquatic polar regions that has been discovered in the last decade, most of which has been revealed by advances in genomics-enabled technologies, and we reflect on the vast extent of the still-to-be explored polar microbial diversity and its “enigmatic virosphere”. Full article
(This article belongs to the Special Issue Viruses of Microbes V: Biodiversity and Future Applications)
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22 pages, 3378 KiB  
Article
Host Resistance, Genomics and Population Dynamics in a Salmonella Enteritidis and Phage System
by Angela Victoria Holguín, Pablo Cárdenas, Catalina Prada-Peñaranda, Laura Rabelo Leite, Camila Buitrago, Viviana Clavijo, Guilherme Oliveira, Pimlapas Leekitcharoenphon, Frank Møller Aarestrup and Martha J. Vives
Viruses 2019, 11(2), 188; https://doi.org/10.3390/v11020188 - 22 Feb 2019
Cited by 19 | Viewed by 6870
Abstract
Bacteriophages represent an alternative solution to control bacterial infections. When interacting, bacteria and phage can evolve, and this relationship is described as antagonistic coevolution, a pattern that does not fit all models. In this work, the model consisted of a microcosm of Salmonella [...] Read more.
Bacteriophages represent an alternative solution to control bacterial infections. When interacting, bacteria and phage can evolve, and this relationship is described as antagonistic coevolution, a pattern that does not fit all models. In this work, the model consisted of a microcosm of Salmonella enterica serovar Enteritidis and φSan23 phage. Samples were taken for 12 days every 48 h. Bacteria and phage samples were collected; and isolated bacteria from each time point were challenged against phages from previous, contemporary, and subsequent time points. The phage plaque tests, with the genomics analyses, showed a mutational asymmetry dynamic in favor of the bacteria instead of antagonistic coevolution. This is important for future phage-therapy applications, so we decided to explore the population dynamics of Salmonella under different conditions: pressure of one phage, a combination of phages, and phages plus an antibiotic. The data from cultures with single and multiple phages, and antibiotics, were used to create a mathematical model exploring population and resistance dynamics of Salmonella under these treatments, suggesting a nonlethal, growth-inhibiting antibiotic may decrease resistance to phage-therapy cocktails. These data provide a deep insight into bacterial dynamics under different conditions and serve as additional criteria to select phages and antibiotics for phage-therapy. Full article
(This article belongs to the Special Issue Diversity and Evolution of Phage Genomes)
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9 pages, 863 KiB  
Article
Tomato Chlorotic Spot Virus (TCSV) Putatively Incorporated a Genomic Segment of Groundnut Ringspot Virus (GRSV) Upon a Reassortment Event
by João Marcos Fagundes Silva, Athos Silva de Oliveira, Mariana Martins Severo de Almeida, Richard Kormelink, Tatsuya Nagata and Renato Oliveira Resende
Viruses 2019, 11(2), 187; https://doi.org/10.3390/v11020187 - 22 Feb 2019
Cited by 8 | Viewed by 5351
Abstract
Tomato chlorotic spot virus (TCSV) and groundnut ringspot virus (GRSV) share several genetic and biological traits. Both of them belong to the genus Tospovirus (family Peribunyaviridae), which is composed by viruses with tripartite RNA genome that infect plants and are transmitted by [...] Read more.
Tomato chlorotic spot virus (TCSV) and groundnut ringspot virus (GRSV) share several genetic and biological traits. Both of them belong to the genus Tospovirus (family Peribunyaviridae), which is composed by viruses with tripartite RNA genome that infect plants and are transmitted by thrips (order Thysanoptera). Previous studies have suggested several reassortment events between these two viruses, and some speculated that they may share one of their genomic segments. To better understand the intimate evolutionary history of these two viruses, we sequenced the genomes of the first TCSV and GRSV isolates ever reported. Our analyses show that TCSV and GRSV isolates indeed share one of their genomic segments, suggesting that one of those viruses may have emerged upon a reassortment event. Based on a series of phylogenetic and nucleotide diversity analyses, we conclude that the parental genotype of the M segment of TCSV was either eliminated due to a reassortment with GRSV or it still remains to be identified. Full article
(This article belongs to the Special Issue Plant Virus Ecology and Biodiversity)
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10 pages, 393 KiB  
Article
Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study
by Sven Pischke, Jean-Marie Peron, Moritz von Wulffen, Johann von Felden, Christoph Höner zu Siederdissen, Sophie Fournier, Marc Lütgehetmann, Christoph Iking-Konert, Dominik Bettinger, Gabriella Par, Robert Thimme, Alain Cantagrel, Ansgar W. Lohse, Heiner Wedemeyer, Robert de Man and Vincent Mallet
Viruses 2019, 11(2), 186; https://doi.org/10.3390/v11020186 - 22 Feb 2019
Cited by 37 | Viewed by 4526
Abstract
Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine [...] Read more.
Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim–Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection. Full article
(This article belongs to the Special Issue Hepatitis E Virus)
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14 pages, 243 KiB  
Review
Co-Infection of Swine with Porcine Circovirus Type 2 and Other Swine Viruses
by Ting Ouyang, Xinwei Zhang, Xiaohua Liu and Linzhu Ren
Viruses 2019, 11(2), 185; https://doi.org/10.3390/v11020185 - 21 Feb 2019
Cited by 136 | Viewed by 9926
Abstract
Porcine circovirus 2 (PCV2) is the etiological agent that causes porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD), which are present in every major swine-producing country in the world. PCV2 infections may downregulate the host immune system and enhance the infection and replication [...] Read more.
Porcine circovirus 2 (PCV2) is the etiological agent that causes porcine circovirus diseases and porcine circovirus-associated diseases (PCVD/PCVAD), which are present in every major swine-producing country in the world. PCV2 infections may downregulate the host immune system and enhance the infection and replication of other pathogens. However, the exact mechanisms of PCVD/PCVAD are currently unknown. To date, many studies have reported that several cofactors, such as other swine viruses or bacteria, vaccination failure, and stress or crowding, in combination with PCV2, lead to PCVD/PCVAD. Among these cofactors, co-infection of PCV2 with other viruses, such as porcine reproductive and respiratory syndrome virus, porcine parvovirus, swine influenza virus and classical swine fever virus have been widely studied for decades. In this review, we focus on the current state of knowledge regarding swine co-infection with different PCV2 genotypes or strains, as well as with PCV2 and other swine viruses. Full article
(This article belongs to the Special Issue Porcine Viruses 2019)
7 pages, 203 KiB  
Article
Estimating Disability-Adjusted Life Years (DALYs) in Community Cases of Norovirus in England
by John P. Harris, Miren Iturriza-Gomara and Sarah J. O’Brien
Viruses 2019, 11(2), 184; https://doi.org/10.3390/v11020184 - 21 Feb 2019
Cited by 5 | Viewed by 4170
Abstract
Disability adjusted life years (DALYs) have been used since the 1990s. It is a composite measure of years of life lost with years lived with disability. Essentially, one DALY is the equivalent of a year of healthy life lost if a person had [...] Read more.
Disability adjusted life years (DALYs) have been used since the 1990s. It is a composite measure of years of life lost with years lived with disability. Essentially, one DALY is the equivalent of a year of healthy life lost if a person had not experienced disease. Norovirus is the most common cause of gastrointestinal diseases worldwide. Norovirus activity varies from one season to the next for reasons not fully explained. Infection with norovirus is generally not severe, and is normally characterized as mild and self-limiting with no long-term sequelae. In this study, we model a range of estimates of DALYs for community cases of norovirus in England and Wales. We estimated a range of DALYs for norovirus to account for mixing of the severity of disease and the range of length of illness experienced by infected people. Our estimates were between 1159 and 4283 DALYs per year, or 0.3–1.2 years of healthy life lost per thousand cases of norovirus. These estimates provide evidence that norovirus leads to a considerable level of ill health in England and Wales. This information will be helpful should candidate norovirus vaccines become available in the future. Full article
(This article belongs to the Special Issue Noroviruses)
18 pages, 1104 KiB  
Article
Development and Characterization of a Sin Nombre Virus Transmission Model in Peromyscus maniculatus
by Bryce M. Warner, Derek R. Stein, Bryan D. Griffin, Kevin Tierney, Anders Leung, Angela Sloan, Darwyn Kobasa, Guillaume Poliquin, Gary P. Kobinger and David Safronetz
Viruses 2019, 11(2), 183; https://doi.org/10.3390/v11020183 - 21 Feb 2019
Cited by 16 | Viewed by 7051
Abstract
In North America, Sin Nombre virus (SNV) is the main cause of hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with a fatality rate of 35–40%. SNV is a zoonotic pathogen carried by deer mice (Peromyscus maniculatus), and few studies have [...] Read more.
In North America, Sin Nombre virus (SNV) is the main cause of hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease with a fatality rate of 35–40%. SNV is a zoonotic pathogen carried by deer mice (Peromyscus maniculatus), and few studies have been performed examining its transmission in deer mouse populations. Studying SNV and other hantaviruses can be difficult due to the need to propagate the virus in vivo for subsequent experiments. We show that when compared with standard intramuscular infection, the intraperitoneal infection of deer mice can be as effective in producing SNV stocks with a high viral RNA copy number, and this method of infection provides a more reproducible infection model. Furthermore, the age and sex of the infected deer mice have little effect on viral replication and shedding. We also describe a reliable model of direct experimental SNV transmission. We examined the transmission of SNV between deer mice and found that direct contact between deer mice is the main driver of SNV transmission rather than exposure to contaminated excreta/secreta, which is thought to be the main driver of transmission of the virus to humans. Furthermore, increases in heat shock responses or testosterone levels in SNV-infected deer mice do not increase the replication, shedding, or rate of transmission. Here, we have demonstrated a model for the transmission of SNV between deer mice, the natural rodent reservoir for the virus. The use of this model will have important implications for further examining SNV transmission and in developing strategies for the prevention of SNV infection in deer mouse populations. Full article
(This article belongs to the Special Issue Hantaviruses)
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18 pages, 2618 KiB  
Review
Mastomys Species as Model Systems for Infectious Diseases
by Daniel Hasche and Frank Rösl
Viruses 2019, 11(2), 182; https://doi.org/10.3390/v11020182 - 21 Feb 2019
Cited by 20 | Viewed by 6127
Abstract
Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo [...] Read more.
Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo situations as found in humans. Despite proven limitations of both approaches, only a combined experimental arrangement guarantees generalizability of results and their transfer to the clinics. Although the laboratory mouse still stands as a paradigm for many scientific discoveries and breakthroughs, it is mandatory to broaden our view by also using nontraditional animal models. The present review will first reflect the value of experimental systems in life science and subsequently describes the preclinical rodent model Mastomys coucha that—although still not well known in the scientific community—has a long history in research of parasites, bacteria, papillomaviruses and cancer. Using Mastomys, we could recently show for the first time that cutaneous papillomaviruses—in conjunction with UV as an environmental risk factor—induce squamous cell carcinomas of the skin via a “hit-and-run” mechanism. Moreover, Mastomys coucha was also used as a proof-of-principle model for the successful vaccination against non-melanoma skin cancer even under immunosuppressive conditions. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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13 pages, 1240 KiB  
Article
Usutu Virus Isolated from Rodents in Senegal
by Moussa Moïse Diagne, Marie Henriette Dior Ndione, Nicholas Di Paola, Gamou Fall, André Pouwedeou Bedekelabou, Pape Mbacké Sembène, Ousmane Faye, Paolo Marinho de Andrade Zanotto and Amadou Alpha Sall
Viruses 2019, 11(2), 181; https://doi.org/10.3390/v11020181 - 21 Feb 2019
Cited by 45 | Viewed by 5723
Abstract
Usutu virus (USUV) is a Culex-associated mosquito-borne flavivirus of the Flaviviridae family. Since its discovery in 1959, the virus has been isolated from birds, arthropods and humans in Europe and Africa. An increasing number of Usutu virus infections in humans with neurological [...] Read more.
Usutu virus (USUV) is a Culex-associated mosquito-borne flavivirus of the Flaviviridae family. Since its discovery in 1959, the virus has been isolated from birds, arthropods and humans in Europe and Africa. An increasing number of Usutu virus infections in humans with neurological presentations have been reported. Recently, the virus has been detected in bats and horses, which deviates from the currently proposed enzootic cycle of USUV involving several different avian and mosquito species. Despite this increasing number of viral detections in different mammalian hosts, the existence of a non-avian reservoir remains unresolved. In Kedougou, a tropical region in the southeast corner of Senegal, Usutu virus was detected, isolated and sequenced from five asymptomatic small mammals: Two different rodent species and a single species of shrew. Additional molecular characterization and in vivo growth dynamics showed that these rodents/shrew-derived viruses are closely related to the reference strain (accession number: AF013412) and are as pathogenic as other characterized strains associated with neurological invasions in human. This is the first evidence of Usutu virus isolation from rodents or shrews. Our findings emphasize the need to consider a closer monitoring of terrestrial small mammals in future active surveillance, public health, and epidemiological efforts in response to USUV in both Africa and Europe. Full article
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14 pages, 3243 KiB  
Article
Global In-Silico Scenario of tRNA Genes and Their Organization in Virus Genomes
by Sergio Morgado and Ana Carolina Vicente
Viruses 2019, 11(2), 180; https://doi.org/10.3390/v11020180 - 21 Feb 2019
Cited by 33 | Viewed by 4468
Abstract
Viruses are known to be highly dependent on the host translation machinery for their protein synthesis. However, tRNA genes are occasionally identified in such organisms, and in addition, few of them harbor tRNA gene clusters comprising dozens of genes. Recently, tRNA gene clusters [...] Read more.
Viruses are known to be highly dependent on the host translation machinery for their protein synthesis. However, tRNA genes are occasionally identified in such organisms, and in addition, few of them harbor tRNA gene clusters comprising dozens of genes. Recently, tRNA gene clusters have been shown to occur among the three domains of life. In such a scenario, the viruses could play a role in the dispersion of such structures among these organisms. Thus, in order to reveal the prevalence of tRNA genes as well as tRNA gene clusters in viruses, we performed an unbiased large-scale genome survey. Interestingly, tRNA genes were predicted in ssDNA (single-stranded DNA) and ssRNA (single-stranded RNA) viruses as well in many other dsDNA viruses of families from Caudovirales order. In the latter group, tRNA gene clusters composed of 15 to 37 tRNA genes were characterized, mainly in bacteriophages, enlarging the occurrence of such structures within viruses. These bacteriophages were from hosts that encompass five phyla and 34 genera. This in-silico study presents the current global scenario of tRNA genes and their organization in virus genomes, contributing and opening questions to be explored in further studies concerning the role of the translation apparatus in these organisms. Full article
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11 pages, 438 KiB  
Article
The Application and Interpretation of IgG Avidity and IgA ELISA Tests to Characterize Zika Virus Infections
by Fátima Amaro, María P. Sánchez-Seco, Ana Vázquez, Maria J. Alves, Líbia Zé-Zé, Maria T. Luz, Teodora Minguito, Jesús De La Fuente and Fernando De Ory
Viruses 2019, 11(2), 179; https://doi.org/10.3390/v11020179 - 20 Feb 2019
Cited by 16 | Viewed by 4257
Abstract
In the absence of viremia, the diagnostics of Zika virus (ZIKV) infections must rely on serological techniques. In order to improve the serological diagnosis of ZIKV, ZIKV-IgA and ZIKV-IgG avidity assays were evaluated. Forty patients returning from ZIKV endemic areas, with confirmed or [...] Read more.
In the absence of viremia, the diagnostics of Zika virus (ZIKV) infections must rely on serological techniques. In order to improve the serological diagnosis of ZIKV, ZIKV-IgA and ZIKV-IgG avidity assays were evaluated. Forty patients returning from ZIKV endemic areas, with confirmed or suspected ZIKV infections were studied. Samples were classified as early acute, acute and late acute according to the number of days post illness onset. Low avidity IgG was only detected at acute and late acute stages and IgA mostly at the early acute and acute stages. The date of sampling provides useful information and can help to choose the best technique to use at a determined moment in time and to interpret low avidity IgG and IgA results, improving the serological diagnosis of ZIKV. Full article
(This article belongs to the Special Issue New Advances on Zika Virus Research)
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14 pages, 2932 KiB  
Article
Molecular Characterization of a Novel Endornavirus Conferring Hypovirulence in Rice Sheath Blight Fungus Rhizoctonia solani AG-1 IA Strain GD-2
by Li Zheng, Canwei Shu, Meiling Zhang, Mei Yang and Erxun Zhou
Viruses 2019, 11(2), 178; https://doi.org/10.3390/v11020178 - 20 Feb 2019
Cited by 45 | Viewed by 4994
Abstract
The complete sequence and genome organization of a novel Endornavirus from the hypovirulent strain GD-2 of Rhizoctonia solani AG-1 IA, the causal agent of rice sheath blight, were identified using a deep sequencing approach and it was tentatively named as Rhizoctonia solani endornavirus [...] Read more.
The complete sequence and genome organization of a novel Endornavirus from the hypovirulent strain GD-2 of Rhizoctonia solani AG-1 IA, the causal agent of rice sheath blight, were identified using a deep sequencing approach and it was tentatively named as Rhizoctonia solani endornavirus 1 (RsEV1). It was composed of only one segment that was 19,936 bp in length and was found to be the longest endornavirus genome that has been reported so far. The RsEV1 genome contained two open reading frames (ORFs): ORF1 and ORF2. ORF1 contained a glycosyltransferase 1 domain and a conserved RNA-dependent RNA polymerase domain, whereas ORF2 encoded a conserved hypothetical protein. Phylogenetic analysis revealed that RsEV1 was phylogenetically a new endogenous RNA virus. A horizontal transmission experiment indicated that RsEV1 could be transmitted from the host fungal strain GD-2 to a virulent strain GD-118P and resulted in hypovirulence in the derivative isogenic strain GD-118P-V1. Metabolomic analysis showed that 32 metabolites were differentially expressed between GD-118P and its isogenic hypovirulent strain GD-118P-V1. The differential metabolites were mainly classified as organic acids, amino acids, carbohydrates, and the intermediate products of energy metabolism. Pathway annotation revealed that these 32 metabolites were mainly involved in pentose and glucuronate interconversions and glyoxylate, dicarboxylate, starch, and sucrose metabolism, and so on. Taken together, our results showed that RsEV1 is a novel Endornavirus, and the infection of virulent strain GD-118P by RsEV1 caused metabolic disorders and resulted in hypovirulence. The results of this study lay a foundation for the biocontrol of rice sheath blight caused by R. solani AG1-IA. Full article
(This article belongs to the Special Issue Plant Virus Ecology and Biodiversity)
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13 pages, 1618 KiB  
Review
GII.4 Human Norovirus: Surveying the Antigenic Landscape
by Michael L. Mallory, Lisa C. Lindesmith, Rachel L. Graham and Ralph S. Baric
Viruses 2019, 11(2), 177; https://doi.org/10.3390/v11020177 - 20 Feb 2019
Cited by 43 | Viewed by 6876
Abstract
Human norovirus is the leading cause of viral acute onset gastroenteritis disease burden, with 685 million infections reported annually. Vulnerable populations, such as children under the age of 5 years, the immunocompromised, and the elderly show a need for inducible immunity, as symptomatic [...] Read more.
Human norovirus is the leading cause of viral acute onset gastroenteritis disease burden, with 685 million infections reported annually. Vulnerable populations, such as children under the age of 5 years, the immunocompromised, and the elderly show a need for inducible immunity, as symptomatic dehydration and malnutrition can be lethal. Extensive antigenic diversity between genotypes and within the GII.4 genotype present major challenges for the development of a broadly protective vaccine. Efforts have been devoted to characterizing antibody-binding interactions with dynamic human norovirus viral-like particles, which recognize distinct antigenic sites on the capsid. Neutralizing antibody functions recognizing these sites have been validated in both surrogate (ligand blockade of binding) and in vitro virus propagation systems. In this review, we focus on GII.4 capsid protein epitopes as defined by monoclonal antibody binding. As additional antibody epitopes are defined, antigenic sites emerge on the human norovirus capsid, revealing the antigenic landscape of GII.4 viruses. These data may provide a road map for the design of candidate vaccine immunogens that induce cross-protective immunity and the development of therapeutic antibodies and drugs. Full article
(This article belongs to the Special Issue Noroviruses)
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26 pages, 2256 KiB  
Article
Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry
by Michela Mazzon, Ana Maria Ortega-Prieto, Douglas Imrie, Christin Luft, Lena Hess, Stephanie Czieso, Joe Grove, Jessica Katy Skelton, Laura Farleigh, Joachim J. Bugert, Edward Wright, Nigel Temperton, Richard Angell, Sally Oxenford, Michael Jacobs, Robin Ketteler, Marcus Dorner and Mark Marsh
Viruses 2019, 11(2), 176; https://doi.org/10.3390/v11020176 - 20 Feb 2019
Cited by 44 | Viewed by 9094
Abstract
Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with [...] Read more.
Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy. Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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26 pages, 945 KiB  
Review
Tropism of the Chikungunya Virus
by Giulia Matusali, Francesca Colavita, Licia Bordi, Eleonora Lalle, Giuseppe Ippolito, Maria R. Capobianchi and Concetta Castilletti
Viruses 2019, 11(2), 175; https://doi.org/10.3390/v11020175 - 20 Feb 2019
Cited by 84 | Viewed by 11617
Abstract
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne virus that displays a large cell and organ tropism, and causes a broad range of clinical symptoms in humans. It is maintained in nature through both urban and sylvatic cycles, involving mosquito vectors and human or [...] Read more.
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne virus that displays a large cell and organ tropism, and causes a broad range of clinical symptoms in humans. It is maintained in nature through both urban and sylvatic cycles, involving mosquito vectors and human or vertebrate animal hosts. Although CHIKV was first isolated in 1953, its pathogenesis was only more extensively studied after its re-emergence in 2004. The unexpected spread of CHIKV to novel tropical and non-tropical areas, in some instances driven by newly competent vectors, evidenced the vulnerability of new territories to this infectious agent and its associated diseases. The comprehension of the exact CHIKV target cells and organs, mechanisms of pathogenesis, and spectrum of both competitive vectors and animal hosts is pivotal for the design of effective therapeutic strategies, vector control measures, and eradication actions. Full article
(This article belongs to the Special Issue Chikungunya Virus and (Re-) Emerging Alphaviruses)
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17 pages, 2168 KiB  
Review
Global Epidemiology of Bat Coronaviruses
by Antonio C. P. Wong, Xin Li, Susanna K. P. Lau and Patrick C. Y. Woo
Viruses 2019, 11(2), 174; https://doi.org/10.3390/v11020174 - 20 Feb 2019
Cited by 254 | Viewed by 33064
Abstract
Bats are a unique group of mammals of the order Chiroptera. They are highly diversified and are the group of mammals with the second largest number of species. Such highly diversified cell types and receptors facilitate them to be potential hosts of [...] Read more.
Bats are a unique group of mammals of the order Chiroptera. They are highly diversified and are the group of mammals with the second largest number of species. Such highly diversified cell types and receptors facilitate them to be potential hosts of a large variety of viruses. Bats are the only group of mammals capable of sustained flight, which enables them to disseminate the viruses they harbor and enhance the chance of interspecies transmission. This article aims at reviewing the various aspects of the global epidemiology of bat coronaviruses (CoVs). Before the SARS epidemic, bats were not known to be hosts for CoVs. In the last 15 years, bats have been found to be hosts of >30 CoVs with complete genomes sequenced, and many more if those without genome sequences are included. Among the four CoV genera, only alphaCoVs and betaCoVs have been found in bats. As a whole, both alphaCoVs and betaCoVs have been detected from bats in Asia, Europe, Africa, North and South America and Australasia; but alphaCoVs seem to be more widespread than betaCoVs, and their detection rate is also higher. For betaCoVs, only those from subgenera Sarbecovirus, Merbecovirus, Nobecovirus and Hibecovirus have been detected in bats. Most notably, horseshoe bats are the reservoir of SARS-CoV, and several betaCoVs from subgenus Merbecovirus are closely related to MERS-CoV. In addition to the interactions among various bat species themselves, bat–animal and bat–human interactions, such as the presence of live bats in wildlife wet markets and restaurants in Southern China, are important for interspecies transmission of CoVs and may lead to devastating global outbreaks. Full article
(This article belongs to the Special Issue Viruses and Bats 2019)
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18 pages, 8738 KiB  
Review
Targeting the Viral Polymerase of Diarrhea-Causing Viruses as a Strategy to Develop a Single Broad-Spectrum Antiviral Therapy
by Marcella Bassetto, Jana Van Dycke, Johan Neyts, Andrea Brancale and Joana Rocha-Pereira
Viruses 2019, 11(2), 173; https://doi.org/10.3390/v11020173 - 20 Feb 2019
Cited by 23 | Viewed by 7022
Abstract
Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against [...] Read more.
Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against any of these pathogens. We here discuss the feasibility of developing a broad-spectrum antiviral treatment against these diarrhea-causing viruses. This review focuses on the viral polymerase as an antiviral target, as this is the most conserved viral protein among the diverse viral families to which these viruses belong to. We describe the functional and structural similarities of the different viral polymerases, the antiviral effect of reported polymerase inhibitors and highlight common features that might be exploited in an attempt of designing such pan-polymerase inhibitor. Full article
(This article belongs to the Special Issue Noroviruses)
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20 pages, 1512 KiB  
Review
Complexities of Type I Interferon Biology: Lessons from LCMV
by Tamara Suprunenko and Markus J. Hofer
Viruses 2019, 11(2), 172; https://doi.org/10.3390/v11020172 - 20 Feb 2019
Cited by 22 | Viewed by 6180
Abstract
Over the past decades, infection of mice with lymphocytic choriomeningitis virus (LCMV) has provided an invaluable insight into our understanding of immune responses to viruses. In particular, this model has clarified the central roles that type I interferons play in initiating and regulating [...] Read more.
Over the past decades, infection of mice with lymphocytic choriomeningitis virus (LCMV) has provided an invaluable insight into our understanding of immune responses to viruses. In particular, this model has clarified the central roles that type I interferons play in initiating and regulating host responses. The use of different strains of LCMV and routes of infection has allowed us to understand how type I interferons are critical in controlling virus replication and fostering effective antiviral immunity, but also how they promote virus persistence and functional exhaustion of the immune response. Accordingly, these discoveries have formed the foundation for the development of novel treatments for acute and chronic viral infections and even extend into the management of malignant tumors. Here we review the fundamental insights into type I interferon biology gained using LCMV as a model and how the diversity of LCMV strains, dose, and route of administration have been used to dissect the molecular mechanisms underpinning acute versus persistent infection. We also identify gaps in the knowledge regarding LCMV regulation of antiviral immunity. Due to its unique properties, LCMV will continue to remain a vital part of the immunologists’ toolbox. Full article
(This article belongs to the Special Issue LCMV – A Pillar for Immunology Research)
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17 pages, 592 KiB  
Review
Influenza Virus Infections and Cellular Kinases
by Robert Meineke, Guus F. Rimmelzwaan and Husni Elbahesh
Viruses 2019, 11(2), 171; https://doi.org/10.3390/v11020171 - 20 Feb 2019
Cited by 79 | Viewed by 11399
Abstract
Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) [...] Read more.
Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways in respond to a myriad of stimuli, including viral infections. Their regulation of multiple response networks has justified actively targeting cellular kinases for anti-cancer therapies and immune modulators for decades. There is a growing volume of research highlighting the significant role of cellular kinases in regulating IAV infections. Their functional role is illustrated by the required phosphorylation of several IAV proteins necessary for replication and/or evasion/suppression of the innate immune response. Identified in the majority of host factor screens, functional studies further support the important role of kinases and their potential as host restriction factors. PKC, ERK, PI3K and FAK, to name a few, are kinases that regulate viral entry and replication. Additionally, kinases such as IKK, JNK and p38 MAPK are essential in mediating viral sensor signaling cascades that regulate expression of antiviral chemokines and cytokines. The feasibility of targeting kinases is steadily moving from bench to clinic and already-approved cancer drugs could potentially be repurposed for treatments of severe IAV infections. In this review, we will focus on the contribution of cellular kinases to IAV infections and their value as potential therapeutic targets. Full article
(This article belongs to the Special Issue Viruses and Cellular Metabolism)
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16 pages, 3341 KiB  
Article
The Three Essential Motifs in P0 for Suppression of RNA Silencing Activity of Potato leafroll virus Are Required for Virus Systemic Infection
by Mamun-Or Rashid, Xiao-Yan Zhang, Ying Wang, Da-Wei Li, Jia-Lin Yu and Cheng-Gui Han
Viruses 2019, 11(2), 170; https://doi.org/10.3390/v11020170 - 20 Feb 2019
Cited by 12 | Viewed by 5030
Abstract
Higher plants exploit posttranscriptional gene silencing as a defense mechanism against virus infection by the RNA degradation system. Plant RNA viruses suppress posttranscriptional gene silencing using their encoded proteins. Three important motifs (F-box-like motif, G139/W140/G141-like motif, and C-terminal conserved region) in P0 of [...] Read more.
Higher plants exploit posttranscriptional gene silencing as a defense mechanism against virus infection by the RNA degradation system. Plant RNA viruses suppress posttranscriptional gene silencing using their encoded proteins. Three important motifs (F-box-like motif, G139/W140/G141-like motif, and C-terminal conserved region) in P0 of Potato leafroll virus (PLRV) were reported to be essential for suppression of RNA silencing activity. In this study, Agrobacterium-mediated transient experiments were carried out to screen the available amino acid substitutions in the F-box-like motif and G139/W140/G141-like motif that abolished the RNA silencing suppression activity of P0, without disturbing the P1 amino acid sequence. Subsequently, four P0 defective mutants derived from a full-length cDNA clone of PLRV (L76F and W87R substitutions in the F-box-like motif, G139RRR substitution in the G139/W140/G141-like motif, and F220R substitution in the C-terminal conserved region) were successfully generated by reverse PCR and used to investigate the impact of these substitutions on PLRV infectivity. The RT-PCR and western blot analysis revealed that these defective mutants affected virus accumulation in inoculated leaves and systemic movement in Nicotiana benthamiana as well as in its natural hosts, potato and black nightshade. These results further demonstrate that the RNA silencing suppressor of PLRV is required for PLRV accumulation and systemic infection. Full article
(This article belongs to the Special Issue Plant Immunity to Virus Infections)
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11 pages, 946 KiB  
Article
A Single-Nucleotide Polymorphism of αVβ3 Integrin Is Associated with the Andes Virus Infection Susceptibility
by Constanza Martínez-Valdebenito, Jenniffer Angulo, Nicole Le Corre, Claudia Marco, Cecilia Vial, Juan Francisco Miquel, Jaime Cerda, Gregory Mertz, Pablo Vial, Marcelo Lopez-Lastra and Marcela Ferrés
Viruses 2019, 11(2), 169; https://doi.org/10.3390/v11020169 - 20 Feb 2019
Cited by 6 | Viewed by 3900
Abstract
The Andes Orthohantavirus (ANDV), which causes the hantavirus cardiopulmonary syndrome, enters cells via integrins, and a change from leucine to proline at residue 33 in the PSI domain (L33P), impairs ANDV recognition. We assessed the association between this human polymorphism and ANDV infection. [...] Read more.
The Andes Orthohantavirus (ANDV), which causes the hantavirus cardiopulmonary syndrome, enters cells via integrins, and a change from leucine to proline at residue 33 in the PSI domain (L33P), impairs ANDV recognition. We assessed the association between this human polymorphism and ANDV infection. We defined susceptible and protective genotypes as “TT” (coding leucine) and “CC” (coding proline), respectively. TT was present at a rate of 89.2% (66/74) among the first cohort of ANDV cases and at 60% (63/105) among exposed close-household contacts, who remained uninfected (p < 0.05). The protective genotype (CC) was absent in all 85 ANDV cases, in both cohorts, and was present at 11.4% of the exposed close-household contacts who remained uninfected. Logistic regression modeling for risk of infection had an OR of 6.2–12.6 (p < 0.05) in the presence of TT and well-known ANDV risk activities. Moreover, an OR of 7.3 was obtained when the TT condition was analyzed for two groups exposed to the same environmental risk. Host genetic background was found to have an important role in ANDV infection susceptibility, in the studied population. Full article
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25 pages, 828 KiB  
Review
Myeloid Cells during Viral Infections and Inflammation
by Ashley A. Stegelmeier, Jacob P. van Vloten, Robert C. Mould, Elaine M. Klafuric, Jessica A. Minott, Sarah K. Wootton, Byram W. Bridle and Khalil Karimi
Viruses 2019, 11(2), 168; https://doi.org/10.3390/v11020168 - 19 Feb 2019
Cited by 77 | Viewed by 9693
Abstract
Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for detecting pathogen-associated molecular patterns, thereby initiating a signaling cascade that results in the production of cytokines such as interferons [...] Read more.
Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for detecting pathogen-associated molecular patterns, thereby initiating a signaling cascade that results in the production of cytokines such as interferons to mitigate infections. The aim of this review is to outline recent advances in our knowledge of the roles that neutrophils and inflammatory monocytes play in initiating and coordinating host responses against viral infections. A focus is placed on myeloid cell development, trafficking and antiviral mechanisms. Although known for promoting inflammation, there is a growing body of literature which demonstrates that myeloid cells can also play critical regulatory or immunosuppressive roles, especially following the elimination of viruses. Additionally, the ability of myeloid cells to control other innate and adaptive leukocytes during viral infections situates these cells as key, yet under-appreciated mediators of pathogenic inflammation that can sometimes trigger cytokine storms. The information presented here should assist researchers in integrating myeloid cell biology into the design of novel and more effective virus-targeted therapies. Full article
(This article belongs to the Special Issue Viruses and Inflammation)
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