The Roles of Apoptosis in Swine Response to Viral Infection and Pathogenesis of Swine Enteropathogenic Coronaviruses

Apoptosis is a tightly regulated mechanism of cell death that plays important roles in various biological processes including biological evolution, multiple system development, anticancer, and viral infections. Swine enteropathogenic coronaviruses invade and damage villous epithelial cells of the small intestine causing severe diarrhea with high mortality rate in suckling piglets. Transmissible gastroenteritis virus (TGEV), Porcine epidemic diarrhea virus (PEDV), Porcine deltacoronavirus (PDCoV), and Swine acute diarrhea syndrome coronavirus (SADS-CoV) are on the top list of commonly-seen swine coronaviruses with a feature of diarrhea, resulting in significant economic losses to the swine industry worldwide. Apoptosis has been shown to be involved in the pathogenesis process of animal virus infectious diseases. Understanding the roles of apoptosis in host responses against swine enteropathogenic coronaviruses infection contribute to disease prevention and control. Here we summarize the recent findings that focus on the apoptosis during swine coronaviruses infection, in particular, TGEV, PEDV, PDCoV, and SADS-CoV.

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Interaction Between PEDV and Its Hosts: A Closer Look at the ORF3 Accessory Protein

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.744276 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yuparat Jantraphakorn ◽

Ratchanont Viriyakitkosol ◽

Anan Jongkaewwattana ◽

Challika Kaewborisuth

Keyword(s):

Vaccine Development ◽

Current Knowledge ◽

Host Responses ◽

Economic Losses ◽

Accessory Protein ◽

Swine Industry ◽

Diarrhea Virus ◽

Functional Studies ◽

Viral Virulence

Porcine epidemic diarrhea virus (PEDV) is a causative agent of a highly contagious enteric disease in swine of all ages, leading to severe economic losses for the swine industry in many countries. One of the most effective approaches in controlling PEDV infection is vaccination. The ORF3 accessory protein has been proposed as a crucial viral virulence factor in a natural host. However, due to the lack of an extensive comparative study of ORF3, exactly how the ORF3 takes part in virus replication and pathogenesis as well as its role in host-virus interaction is unclear. In this review, we aim to discuss the current knowledge of ORF3 concerning its dispensability for viral replication in vitro, ability to modulate host responses, contribution to virus pathogenicity, and research gaps among ORF3 functional studies. These will be beneficial for further studies to a better understanding of PEDV biology and PEDV vaccine development.

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MicroRNA-376b-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication by Targeting Viral Restriction Factor TRIM22

Journal of Virology ◽

10.1128/jvi.01597-21 ◽

2021 ◽

Author(s):

Jing Chen ◽

Shijie Zhao ◽

Zhiying Cui ◽

Wen Li ◽

Pengli Xu ◽

...

Keyword(s):

Viral Infections ◽

Antiviral Effect ◽

Economic Losses ◽

Respiratory Syndrome Virus ◽

Restriction Factor ◽

Transcriptional Level ◽

Swine Industry ◽

Human Virus ◽

N Protein ◽

Novel Strategy

Porcine reproductive and respiratory syndrome virus is a major economically significant pathogen and has evolved several strategies to evade host's antiviral response and provide favorable conditions for survival. In the present study, we demonstrated that a host microRNA, miR-376b-3p, was upregulated by PRRSV infection through the viral components, nsp4 and nsp11, and miR-376b-3p can directly target tripartite motif-containing 22 (TRIM22) to impair its anti-PRRSV activity, thus facilitating the replication of PRRSV. Meanwhile, we found that TRIM22 induced degradation of the nucleocapsid protein (N) of PRRSV by interacting with N protein to inhibit PRRSV replication, and further study indicated that TRIM22 could enhance the activation of lysosomal pathway by interacting with LC3 to induce lysosomal degradation of N protein. In conclusion, PRRSV increased miR-376b-3p expression and hijacked the host miR-376b-3p to promote PRRSV replication by impairing the antiviral effect of TRIM22. Therefore, our finding outlines a novel strategy of immune evasion exerted by PRRSV, which is helpful for better understanding the pathogenesis of PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes enormous economic losses each year in the swine industry worldwide. MicroRNAs (miRNAs) play important roles during viral infections via modulating the expression of viral or host genes at post-transcriptional level. TRIM22 has recently been identified as a key restriction factor that inhibited the replication of a number of human virus such as HIV, ECMV, HCV, HBV, IAV, and RSV. Here we showed that host miR-376b-3p could be up-regulated by PRRSV and functioned to impair the anti-PRRSV role of TRIM22 to facilitate PRRSV replication. Meanwhile, we found that TRIM22 inhibited the replication of PRRSV by interacting with viral N protein and accelerating its degradation through the lysosomal pathway. Collectively, the paper described a novel mechanism that PRRSV exploited the host miR-376b-3p to evade antiviral responses and provided a new insight into the study of virus-host interactions.

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Nanoparticle-based vaccine development and evaluation against viral infections in pigs

Veterinary Research ◽

10.1186/s13567-019-0712-5 ◽

2019 ◽

Vol 50 (1) ◽

Cited By ~ 8

Author(s):

Santosh Dhakal ◽

Gourapura J. Renukaradhya

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Protective Efficacy ◽

Vaccine Delivery ◽

Field Conditions ◽

Economic Losses ◽

Virus Infections ◽

Trade Restrictions ◽

Diarrhea Virus ◽

Mouth Disease Virus

Abstract Virus infections possess persistent health challenges in swine industry leading to severe economic losses worldwide. The economic burden caused by virus infections such as Porcine Reproductive and Respiratory Syndrome Virus, Swine influenza virus, Porcine Epidemic Diarrhea Virus, Porcine Circovirus 2, Foot and Mouth Disease Virus and many others are associated with severe morbidity, mortality, loss of production, trade restrictions and investments in control and prevention practices. Pigs can also have a role in zoonotic transmission of some viral infections to humans. Inactivated and modified-live virus vaccines are available against porcine viral infections with variable efficacy under field conditions. Thus, improvements over existing vaccines are necessary to: (1) Increase the breadth of protection against evolving viral strains and subtypes; (2) Control of emerging and re-emerging viruses; (3) Eradicate viruses localized in different geographic areas; and (4) Differentiate infected from vaccinated animals to improve disease control programs. Nanoparticles (NPs) generated from virus-like particles, biodegradable and biocompatible polymers and liposomes offer many advantages as vaccine delivery platform due to their unique physicochemical properties. NPs help in efficient antigen internalization and processing by antigen presenting cells and activate them to elicit innate and adaptive immunity. Some of the NPs-based vaccines could be delivered through both parenteral and mucosal routes to trigger efficient mucosal and systemic immune responses and could be used to target specific immune cells such as mucosal microfold (M) cells and dendritic cells (DCs). In conclusion, NPs-based vaccines can serve as novel candidate vaccines against several porcine viral infections with the potential to enhance the broader protective efficacy under field conditions. This review highlights the recent developments in NPs-based vaccines against porcine viral pathogens and how the NPs-based vaccine delivery system induces innate and adaptive immune responses resulting in varied level of protective efficacy.

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Genomics of Avian Viral Infections

Genes ◽

10.3390/genes10100814 ◽

2019 ◽

Vol 10 (10) ◽

pp. 814 ◽

Cited By ~ 1

Author(s):

Smith

Keyword(s):

Viral Infections ◽

Current Knowledge ◽

Host Susceptibility ◽

Host Responses ◽

Economic Losses ◽

Poultry Industry ◽

Special Issue ◽

Viral Pathogens ◽

Genetic Mechanisms ◽

Global Population

The poultry industry currently accounts for the production of around 118 million metric tons of meat and around 74 million metric tons of eggs annually. As the global population continues to increase, so does our reliance on poultry as a food source. It is therefore of vital importance that we safeguard this valuable resource and make the industry as economically competitive as possible. Avian viral infections, however, continue to cost the poultry industry billions of dollars annually. This can be in terms of vaccination costs, loss of birds and decreased production. With a view to improving the health and welfare of commercial birds and to minimizing associated economic losses, it is therefore of great importance that we try to understand the genetic mechanisms underlying host susceptibility and resilience to some of the major viral pathogens that threaten the poultry species. Some avian viruses, through their zoonotic potential, also pose a risk to human health. This Special Issue will present papers that describe our current knowledge on host responses to various viral pathogens, the genetics underlying those responses and how genomics can begin to provide a solution for resolving the threat posed by these infections.

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THE OUTBREAK OF PORCINE EPIDEMIC DIARRHEA IN TAIWAN

Taiwan Veterinary Journal ◽

10.1142/s1682648514500188 ◽

2014 ◽

Vol 40 (03) ◽

pp. 115-121 ◽

Cited By ~ 1

Author(s):

Ming-Chung Deng ◽

Chia-Yi Chang ◽

Tien-Shine Huang ◽

Shu-Ting Kuo ◽

Hsiang-Jung Tsai ◽

...

Keyword(s):

Animal Health ◽

Vero Cells ◽

Transmissible Gastroenteritis Virus ◽

Rt Pcr ◽

Sequence Comparisons ◽

Diarrhea Virus ◽

Severe Diarrhea ◽

Porcine Epidemic Diarrhea ◽

Transmissible Gastroenteritis ◽

Group 2

Between January 20 and April 30 of 2014, a total of 103 diarrhea cases from 47 herds in 13 counties were submitted to the Animal Health Research Institute. In 20 of the 25 herds with detail history, severe diarrhea and vomiting occurred in pigs of all ages, with mortality approaching 100% in suckling pigs. The differential etiologies, including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine group A rotavirus (GARV), were tested by reverse transcription polymerase chain reaction (RT-PCR). The RT-PCR of PEDV was positive in 79 cases of 34 herds. Attempts to isolate PEDV in Vero cells revealed that only 7 specimens from 7 herds showed the cytopathic effects (CPEs) of fusion and syncytia. These CPEs were indeed caused by PEDV, as confirmed by RT-PCR, sequencing, and electron microscopy. Sequence comparisons of diarrhea samples and isolated PEDV were assayed by MEGA 5.2 software. The newly isolated PEDV/Taiwan/2014 strains were clustered in group 2 as novel PEDV, together with strains PEDV/USA/2013, PEDV/China/2011–2013, PEDV/Thailand/2007–2008, and PEDV/Korea/2008–2009, whereas the classical CV777 strain was placed in a separate group 1. These results indicated that a novel PEDV was the cause of the recent new outbreak of diarrhea in Taiwan.

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Molecular Characteristics and Pathogenicity of Porcine Epidemic Diarrhea Virus Isolated in Some Areas of China in 2015–2018

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.607662 ◽

2020 ◽

Vol 7 ◽

Author(s):

Linyang Yu ◽

Yanling Liu ◽

Shuangyun Wang ◽

Leyi Zhang ◽

Pengshuai Liang ◽

...

Keyword(s):

Porcine Epidemic Diarrhea Virus ◽

Vero Cells ◽

Economic Losses ◽

Molecular Characteristics ◽

Phylogenetic Tree Analysis ◽

Genetic Characteristics ◽

Diarrhea Virus ◽

Severe Diarrhea ◽

Positive Rate ◽

Porcine Epidemic Diarrhea

Since 2010, Porcine epidemic diarrhea virus (PEDV) has caused severe diarrhea disease in piglets in China, resulting in large economic losses. To understand the genetic characteristics of the PEDV strains that circulated in some provinces of China between 2015 and 2018, 375 samples of feces and small intestine were collected from pigs and tested. One hundred seventy-seven samples tested positive and the PEDV-positive rate was 47.20%. A phylogenetic tree analysis based on the entire S gene showed that these strains clustered into four subgroups, GI-a, GI-b, GII-a, and GII-b, and that the GII-b strains have become dominant in recent years. Compared with previous strains, these strains have multiple variations in the SP and S1-NTD domains and in the neutralizing epitopes of the S protein. We also successfully isolated and identified a new virulent GII-b strain, GDgh16, which is well-adapted to Vero cells and caused a high mortality rate in piglets in challenge experiments. Our study clarifies the genetic characteristics of the prevalent PEDV strains in parts of China, and suggests that the development of effective novel vaccines is both necessary and urgent.

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Prevalence and phylogenetic analysis of porcine diarrhea associated viruses in southern China from 2012 to 2018

BMC Veterinary Research ◽

10.1186/s12917-019-2212-2 ◽

2019 ◽

Vol 15 (1) ◽

Cited By ~ 6

Author(s):

Fanfan Zhang ◽

Suxian Luo ◽

Jun Gu ◽

Zhiquan Li ◽

Kai Li ◽

...

Keyword(s):

Phylogenetic Analysis ◽

Large Scale ◽

Southern China ◽

Genetic Relationships ◽

Transmissible Gastroenteritis Virus ◽

Prevalence Rates ◽

Spike Gene ◽

Diarrhea Virus ◽

Severe Diarrhea ◽

The Usa

Abstract Background In China, large-scale outbreaks of severe diarrhea caused by viruses have occurred in pigs since late 2010. To investigate the prevalence and genetic evolution of diarrhea-associated viruses responsible for the outbreaks, a total of 2987 field diarrheal samples collected from 168 pig farms in five provinces in Southern China during 2012–2018 were tested. Results Porcine epidemic diarrhea virus (PEDV) was most frequently detected virus with prevalence rates between 50.21 and 62.10% in samples, and 96.43% (162/168) in premises, respectively. Porcine deltacoronavirus (PDCoV) was the second prevalent virus with prevalence rates ranging from 19.62 to 29.19% in samples, and 70.24% (118/168) in premises, respectively. Both transmissible gastroenteritis virus (TGEV) and porcine rotavirus (PoRV) were detected at low prevalence rates of < 3% in samples and 10.12% in premises. In this study, we identified a newly emerged swine acute diarrhea syndrome coronavirus (SADS-CoV) in diarrheal samples of piglets from Fujian province in Southern China, and the prevalence rate of SADS-CoV was 10.29% (7/68). Co-infections of these diarrhea-associated viruses were common. The most frequent co-infection was PEDV with PDCoV, with an average detection rate of 12.72% (380/2987, ranging from 8.26–17.33%). Phylogenetic analysis revealed that PEDVs circulating in Southern China during the last 7 years were clustered with the variant strains of PEDV in genotype IIa. The most frequent mutations were present in the collagenase equivalent (COE) and epitope regions of the spike gene of the PEDVs currently circulating in the field. Genetic relationships of PDCoVs were closely related with Chinese strains, other than those present in the USA, South Korea, Thailand and Lao’s public. Conclusions The findings of this study indicated that variant PEDV, PDCoV, and SADS-CoV were leading etiologic agents of porcine diarrhea, and either mono-infections or co-infections of pathogenic enteric CoVs were common in pigs in Southern China during 2012–2018. Thus, significant attention should be paid in order to effectively prevent and control porcine viral diarrhea.

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Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease

Veterinary Research ◽

10.1186/s13567-020-00865-y ◽

2020 ◽

Vol 51 (1) ◽

Author(s):

Pengcheng Wang ◽

Juan Bai ◽

Xuewei Liu ◽

Mi Wang ◽

Xianwei Wang ◽

...

Keyword(s):

Porcine Epidemic Diarrhea Virus ◽

Economic Losses ◽

Titration Calorimetry ◽

Respiratory Syndrome Virus ◽

Transmissible Gastroenteritis Virus ◽

Diarrhea Virus ◽

Infected Cells ◽

Porcine Epidemic Diarrhea ◽

3Cl Protease

Abstract Porcine epidemic diarrhea virus (PEDV) causes lethal diarrhea in suckling piglets, leading to severe economic losses worldwide. There is an urgent need to find new therapeutic methods to prevent and control PEDV. Not only is there a shortage of commercial anti-PEDV drugs, but available commercial vaccines fail to protect against highly virulent PEDV variants. We screened an FDA-approved library of 911 natural products and found that tomatidine, a steroidal alkaloid extracted from the skin and leaves of tomatoes, demonstrates significant inhibition of PEDV replication in Vero and IPEC-J2 cells in vitro. Molecular docking and molecular dynamics analysis predicted interactions between tomatidine and the active pocket of PEDV 3CL protease, which were confirmed by fluorescence spectroscopy and isothermal titration calorimetry (ITC). The inhibiting effect of tomatidine on 3CL protease was determined using cleavage visualization and FRET assay. Tomatidine-mediated blocking of 3CL protease activity in PEDV-infected cells was examined by western blot detection of the viral polyprotein in PEDV-infected cells. It indicates that tomatidine inhibits PEDV replication mainly by targeting 3CL protease. In addition, tomatidine also has antiviral activity against transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), encephalo myocarditis virus (EMCV) and seneca virus A (SVA) in vitro. These results may be helpful in developing a new prophylactic and therapeutic strategy against PEDV and other swine disease infections.

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Development of a droplet digital PCR for detection and quantification of porcine epidemic diarrhea virus

Journal of Veterinary Diagnostic Investigation ◽

10.1177/1040638720924753 ◽

2020 ◽

Vol 32 (4) ◽

pp. 572-576 ◽

Cited By ~ 1

Author(s):

Wei W. Cao ◽

Dong S. He ◽

Zhen J. Chen ◽

Yu Z. Zuo ◽

Xun Chen ◽

...

Keyword(s):

Porcine Epidemic Diarrhea Virus ◽

Fold Increase ◽

Digital Pcr ◽

Droplet Digital Pcr ◽

Economic Losses ◽

Swine Industry ◽

Diarrhea Virus ◽

Viral Loads ◽

Promising Tool ◽

Porcine Epidemic Diarrhea

Porcine epidemic diarrhea, a disease caused by porcine epidemic diarrhea virus (PEDV), results in large economic losses to the global swine industry. To manage this disease effectively, it is essential to detect PEDV early and accurately. We developed a sensitive and accurate droplet digital PCR (ddPCR) assay to detect PEDV. The optimal primer-to-probe concentration and melting temperature were identified as 300:200 nM and 59.2°C, respectively. The specificity of the ddPCR assay was confirmed by negative test results for common swine pathogens. The detection limit for the ddPCR was 0.26 copies/μL, which is a 5.7-fold increase in sensitivity compared to that of real-time PCR (rtPCR). Both ddPCR and rtPCR assays exhibited good linearity, although ddPCR provided higher sensitivity for clinical detection compared to that of rtPCR. Our ddPCR methodology provides a promising tool for evaluating the PEDV viral load when used for clinical testing, particularly for detecting samples with low-copy viral loads.

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Porcine Epidemic Diarrhea Virus 3C-Like Protease-Mediated Nucleocapsid Processing: Possible Link to Viral Cell Culture Adaptability

Journal of Virology ◽

10.1128/jvi.01660-16 ◽

2016 ◽

Vol 91 (2) ◽

Cited By ~ 10

Author(s):

Peera Jaru-Ampornpan ◽

Juggragarn Jengarn ◽

Asawin Wanitchang ◽

Anan Jongkaewwattana

Keyword(s):

Cell Culture ◽

Growth Retardation ◽

Porcine Epidemic Diarrhea Virus ◽

Vaccine Development ◽

Wild Type Virus ◽

Economic Losses ◽

Swine Industry ◽

Diarrhea Virus ◽

Porcine Epidemic Diarrhea

ABSTRACT Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high mortality rates in newborn piglets, leading to massive losses to the swine industry worldwide during recent epidemics. Intense research efforts are now focusing on defining viral characteristics that confer a growth advantage, pathogenicity, or cell adaptability in order to better understand the PEDV life cycle and identify suitable targets for antiviral or vaccine development. Here, we report a unique phenomenon of PEDV nucleocapsid (N) cleavage by the PEDV-encoded 3C-like protease (3Cpro) during infection. The identification of the 3Cpro cleavage site at the C terminus of N supported previous observations that PEDV 3Cpro showed a substrate requirement slightly different from that of severe acute respiratory syndrome coronavirus (SARS-CoV) 3Cpro and revealed a greater flexibility in its substrate recognition site. This cleavage motif is present in the majority of cell culture-adapted PEDV strains but is missing in emerging field isolates. Remarkably, reverse-genetics-derived cell culture-adapted PEDVAVCT12 harboring uncleavable N displayed growth retardation in Vero E6-APN cells compared to the wild-type virus. These observations altogether shed new light on the investigation and characterization of the PEDV nucleocapsid protein and its possible link to cell culture adaptation. IMPORTANCE Recurrent PEDV outbreaks have resulted in enormous economic losses to swine industries worldwide. To gain the upper hand in combating this disease, it is necessary to understand how this virus replicates and evades host immunity. Characterization of viral proteins provides important clues to mechanisms by which viruses survive and spread. Here, we characterized an intriguing phenomenon in which the nucleocapsids of some PEDV strains are proteolytically processed by the virally encoded main protease. Growth retardation in recombinant PEDV carrying uncleavable N suggests a replication advantage provided by the cleavage event, at least in the cell culture system. These findings may direct us to a more complete understanding of PEDV replication and pathogenicity.

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