•Evolution of global PEDV strains.•Cross-reactivity between PEDV and other coronaviruses and antigenic variations among different PEDV strains.•Pathologic features of different PEDV ...strains.•Considerations for vaccine strain selection: PEDV virulence attenuation and in vivo cross-protection among PEDV variants.
Emerging and re-emerging coronaviruses cause morbidity and mortality in human and animal populations, resulting in serious public and animal health threats and economic losses. The ongoing outbreak of a highly contagious and deadly porcine epidemic diarrhea virus (PEDV) in Asia, the Americas and Europe is one example. Genomic sequence analyses of PEDV variants have revealed important insights into the evolution of PEDV. However, the antigenic variations among different PEDV strains are less explored, although they may contribute to the failure of PEDV vaccines in Asian countries. In addition, the evolution of PEDV results in variants with distinct genetic features and virulence differences; thus PEDV can serve as a model to explore the molecular mechanisms of coronavirus evolution and pathogenesis. In this article, we review the evolution, antigenic relationships and pathologic features of PEDV strains. This information and review of researches will aid in the development of strategies for control and prevention of PED.
The porcine epidemic diarrhoea virus (PEDV), a member of the Coronaviridae family, causes acute diarrhoea and dehydration in pigs. Although it was first identified in Europe, it has become ...increasingly problematic in many Asian countries, including Korea, China, Japan, the Philippines, and Thailand. The economic impacts of the PEDV are substantial, given that it results in significant morbidity and mortality in neonatal piglets and is associated with increased costs related to vaccination and disinfection. Recently, progress has been made in understanding the molecular epidemiology of PEDV, thereby leading to the development of new vaccines. In the current review, we first describe the molecular and genetic characteristics of the PEDV. Then we discuss its molecular epidemiology and diagnosis, what vaccines are available, and how PEDV can be treated.
A wide-ranging study that illuminates the connection between epidemic diseases and societal change, from the Black Death to Ebola This sweeping exploration of the impact of epidemic diseases looks at ...how mass infectious outbreaks have shaped society, from the Black Death to today. In a clear and accessible style, Frank M. Snowden reveals the ways that diseases have not only influenced medical science and public health, but also transformed the arts, religion, intellectual history, and warfare. A multidisciplinary and comparative investigation of the medical and social history of the major epidemics, this volume touches on themes such as the evolution of medical therapy, plague literature, poverty, the environment, and mass hysteria. In addition to providing historical perspective on diseases such as smallpox, cholera, and tuberculosis, Snowden examines the fallout from recent epidemics such as HIV/AIDS, SARS, and Ebola and the question of the world's preparedness for the next generation of diseases.
•Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea, dehydration and high mortality in neonatal pig.•S INDEL and non-S INDEL strains were detected during the diarrheal disease outbreak in ...US swine in 2013–2014.•The non-S INDEL PEDV was highly virulent, whereas the S INDEL PEDV caused milder disease.•The main PEDV transmission route is fecal–oral, but airborne transmission via the fecal–nasal route may also occur.•PEDV-specific IgA effector and memory B cells in orally primed sows play a critical role in sow lactogenic immunity.
Porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus in the family Coronaviridae, causes acute diarrhea and/or vomiting, dehydration and high mortality in neonatal piglets. Two different genogroups of PEDV, S INDEL PEDV variant containing multiple deletions and insertions in the S1 subunit of the spike (S) protein, G1b and non-S INDEL (G2b) strains were detected during the diarrheal disease outbreak in US swine in 2013–2014. Similar viruses are also circulating globally. Continuous improvement and update of biosecurity and vaccine strains and protocols are still needed to control and prevent PEDV infections worldwide. Although the non-S INDEL PEDV was highly virulent and the S INDEL PEDV caused milder disease, the latter has the capacity to cause illness in a high number of piglets on farms with low biosecurity and herd immunity. The main PEDV transmission route is fecal–oral, but airborne transmission via the fecal–nasal route may play a role in pig-to-pig and farm-to-farm spread. PEDV infection of neonatal pigs causes fecal virus shedding (alongside frequent detection of PEDV RNA in the nasal cavity), acute viremia, severe atrophic enteritis (mainly jejunum and ileum), and increased pro-inflammatory and innate immune responses. PEDV-specific IgA effector and memory B cells in orally primed sows play a critical role in sow lactogenic immunity and passive protection of piglets. This review focuses on the etiology, transmission, pathogenesis, and prevention and control of PEDV infection.
Porcine epidemic diarrhea virus (PEDV) causes enteric disease in pigs, resulting in significant economic losses to the swine industry worldwide. Current vaccination approaches against this emerging ...coronavirus are only partially effective, though natural infection protects pigs against reinfection and provides lactogenic immunity to suckling piglets. The viral spike (S) glycoprotein, responsible for receptor binding and cell entry, is the major target for neutralizing antibodies. However, knowledge of antibody epitopes, their nature and location in the spike structure, and the mechanisms by which the antibodies interfere with infection is scarce. Here we describe the generation and characterization of 10 neutralizing and nonneutralizing mouse monoclonal antibodies raised against the S1 receptor binding subunit of the S protein. By expression of different S1 protein fragments, six antibody epitope classes distributed over the five structural domains of the S1 subunit were identified. Characterization of antibodies for cross-reactivity and cross-neutralization revealed antigenic differences among PEDV strains. The epitopes of potent neutralizing antibodies segregated into two epitope classes and mapped within the N-terminal sialic acid binding domain and in the more C-terminal receptor binding domain. Antibody neutralization escape mutants displayed single amino acid substitutions that impaired antibody binding and neutralization and defined the locations of the epitopes. Our observations picture the antibody epitope landscape of the PEDV S1 subunit and reveal that its cell attachment domains are key targets of neutralizing antibodies.
Porcine epidemic diarrhea virus (PEDV), an emerging porcine coronavirus, causes an economically important enteric disease in pigs. Effective PEDV vaccines for disease control are currently lacking. The spike (S) glycoprotein on the virion surface is the key player in virus cell entry and, therefore, the main target of neutralizing antibodies. To understand the antigenic landscape of the PEDV spike protein, we developed monoclonal antibodies against the spike protein's S1 receptor binding region and characterized their epitopes, neutralizing activity, and cross-reactivity toward multiple PEDV strains. Epitopes of antibodies segregated into six epitope classes dispersed over the multidomain S1 structure. Monoclonal antibodies revealed antigenic variability in B-cell epitopes between PEDV strains. The epitopes of neutralizing antibodies mapped to two distinct domains in S1 that are involved in binding to carbohydrate and proteinaceous cell surface molecules, respectively, indicating the importance of these cell attachment sites on the PEDV spike protein in eliciting a protective humoral immune response.
The present work deals with an Ordinary Differential Equation (ODE) model specifically designed to describe the COVID-19 evolution in Italy. The model is particularised on the basis of National data ...about the infection status of the Italian population to obtain numerical solutions that effectively reproduce the real data. Our epidemic model is a classical SEIR model that incorporates two compartments of infected subpopulations, representing diagnosed and undiagnosed individuals respectively, and an additional quarantine compartment. Possible control actions representing social, political, and medical interventions are also included. The numerical results of the proposed model identification by least square fitting are analysed and commented with special emphasis on the estimation of the number of asymptomatic infective individuals. Our fitting results are in good agreement with the epidemiological data. Short and long-term predictions on the evolution of the disease are also given.
Mathematical modeling is critical to our understanding of how infectious diseases spread at the individual and population levels. This book gives readers the necessary skills to correctly formulate ...and analyze mathematical models in infectious disease epidemiology, and is the first treatment of the subject to integrate deterministic and stochastic models and methods.
Mathematical Tools for Understanding Infectious Disease Dynamicsfully explains how to translate biological assumptions into mathematics to construct useful and consistent models, and how to use the biological interpretation and mathematical reasoning to analyze these models. It shows how to relate models to data through statistical inference, and how to gain important insights into infectious disease dynamics by translating mathematical results back to biology. This comprehensive and accessible book also features numerous detailed exercises throughout; full elaborations to all exercises are provided.
Covers the latest research in mathematical modeling of infectious disease epidemiologyIntegrates deterministic and stochastic approachesTeaches skills in model construction, analysis, inference, and interpretationFeatures numerous exercises and their detailed elaborationsMotivated by real-world applications throughout
We previously isolated a porcine epidemic diarrhea virus (PEDV) strain, PC177, by blind serial passaging of the intestinal contents of a diarrheic piglet in Vero cell culture. Compared with the ...highly virulent U.S. PEDV strain PC21A, the tissue culture-adapted PC177 (TC-PC177) contains a 197-amino-acid (aa) deletion in the N-terminal domain of the spike (S) protein. We orally inoculated neonatal, conventional suckling piglets with TC-PC177 or PC21A to compare their pathogenicities. Within 7 days postinoculation, TC-PC177 caused mild diarrhea and lower fecal viral RNA shedding, with no mortality, whereas PC21A caused severe clinical signs and 55% mortality. To investigate whether infection with TC-PC177 can induce cross-protection against challenge with a highly virulent PEDV strain, all the surviving piglets were challenged with PC21A at 3 weeks postinoculation. Compared with 100% protection in piglets initially inoculated with PC21A, 88% and 100% TC-PC177- and mock-inoculated piglets had diarrhea following challenge, respectively, indicating incomplete cross-protection. To investigate whether this 197-aa deletion was the determinant for the attenuation of TC-PC177, we generated a mutant (icPC22A-S1Δ197) bearing the 197-aa deletion from an infectious cDNA clone of the highly virulent PEDV PC22A strain (infectious clone PC22A, icPC22A). In neonatal gnotobiotic pigs, the icPC22A-S1Δ197 virus caused mild to moderate diarrhea, lower titers of viral shedding, and no mortality, whereas the icPC22A virus caused severe diarrhea and 100% mortality. Our data indicate that deletion of this 197-aa fragment in the spike protein can attenuate a highly virulent PEDV, but the virus may lose important epitopes for inducing robust protective immunity.
The emerging, highly virulent PEDV strains have caused substantial economic losses worldwide. However, the virulence determinants are not established. In this study, we found that a 197-aa deletion in the N-terminal region of the S protein did not alter virus (TC-PC177) tissue tropism but reduced the virulence of the highly virulent PEDV strain PC22A in neonatal piglets. We also demonstrated that the primary infection with TC-PC177 failed to induce complete cross-protection against challenge by the highly virulent PEDV PC21A, suggesting that the 197-aa region may contain important epitopes for inducing protective immunity. Our results provide an insight into the role of this large deletion in virus propagation and pathogenicity. In addition, the reverse genetics platform of the PC22A strain was further optimized for the rescue of recombinant PEDV viruses
This breakthrough allows us to investigate other virulence determinants of PEDV strains and will provide knowledge leading to better control PEDV infections.
Porcine epidemic diarrhea virus (PEDV), which emerged in the United States in 2013, has spread throughout North America. Limited availability of PEDV complete genomes worldwide has impeded our ...understanding of PEDV introduction into the United States. To determine the relationship between the North American strains and global emerging and historic PEDV strains, we sequenced and analyzed complete genomes of 74 strains from North America; the strains clustered into 2 distinct clades. Compared with the initially reported virulent US PEDV strains, 7 (9.7%) strains from 4 states contained insertions and deletions in the spike gene (S INDELs). These S INDEL strains share 99.8%-100% nt identity with each other and 96.2%-96.7% nt identity with the initial US strains. Furthermore, the S INDEL strains form a distinct cluster within North American clade II, sharing 98.6%-100% nt identity overall. In the United States, the S INDEL and original PEDV strains are co-circulating and could have been introduced simultaneously.
Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus. The first outbreak of PDCoV was announced from the United States in 2014, followed by reports in Asia. The ...nonstructural protein nsp5 is a 3C-like protease of coronavirus, and our previous study showed that PDCoV nsp5 inhibits type I interferon (IFN) production. In this study, we found that PDCoV nsp5 significantly inhibited IFN-stimulated response element (ISRE) promoter activity and transcription of IFN-stimulated genes (ISGs), suggesting that PDCoV nsp5 also suppresses IFN signaling. Detailed analysis showed that nsp5 cleaved signal transducer and activator of transcription 2 (STAT2) but not Janus kinase 1 (JAK1), tyrosine kinase 2 (TYK2), STAT1, and interferon regulatory factor 9 (IRF9), key molecules of the JAK-STAT pathway. STAT2 cleavage was dependent on the protease activity of nsp5. Interestingly, nsp5 cleaved STAT2 at two sites, glutamine 685 (Q685) and Q758, and similar cleavage was observed in PDCoV-infected cells. As expected, cleaved STAT2 impaired the ability to induce ISGs, demonstrating that STAT2 cleavage is an important mechanism utilized by PDCoV nsp5 to antagonize IFN signaling. We also discussed the substrate selection and binding mode of PDCoV nsp5 by homologous modeling of PDCoV nsp5 with the two cleaved peptide substrates. The results of our study demonstrate that PDCoV nsp5 antagonizes type I IFN signaling by cleaving STAT2 and provides structural insights for comprehending the cleavage mechanism of PDCoV nsp5, revealing a potential new function for PDCoV nsp5 in type I IFN signaling.
The 3C-like protease encoded by nsp5 is a major protease of coronaviruses; thus, it is an attractive target for development of anticoronavirus drugs. Previous studies have revealed that the 3C-like protease of coronaviruses, including PDCoV and porcine epidemic diarrhea virus (PEDV), antagonizes type I IFN production by targeting the NF-κB essential modulator (NEMO). Here, for the first time, we demonstrate that overexpression of PDCoV nsp5 also antagonizes IFN signaling by cleaving STAT2, an essential component of transcription factor complex ISGF3, and that PDCoV infection reduces the levels of STAT2, which may affect the innate immune response.