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Journal of Virology Nov 2023As an emerging porcine enteropathogenic coronavirus that has the potential to infect humans, porcine deltacoronavirus (PDCoV) is receiving increasing attention. However,...
As an emerging porcine enteropathogenic coronavirus that has the potential to infect humans, porcine deltacoronavirus (PDCoV) is receiving increasing attention. However, no effective commercially available vaccines against this virus are available. In this work, we designed a spike (S) protein and receptor-binding domain (RBD) trimer as a candidate PDCoV subunit vaccine. We demonstrated that S protein induced more robust humoral and cellular immune responses than the RBD trimer in mice. Furthermore, the protective efficacy of the S protein was compared with that of inactivated PDCoV vaccines in piglets and sows. Of note, the immunized piglets and suckling pig showed a high level of NAbs and were associated with reduced virus shedding and mild diarrhea, and the high level of NAbs was maintained for at least 4 months. Importantly, we demonstrated that S protein-based subunit vaccines conferred significant protection against PDCoV infection.
Topics: Animals; Female; Humans; Mice; Coronavirus; Coronavirus Infections; Deltacoronavirus; Swine; Swine Diseases; Vaccines, Subunit
PubMed: 37846983
DOI: 10.1128/jvi.00958-23 -
Emerging Microbes & Infections Dec 2023Porcine deltacoronavirus (PDCoV) is an emerging enteric coronavirus that has been reported to infect a variety of animals and even humans. Cell-cell fusion has been...
Porcine deltacoronavirus (PDCoV) is an emerging enteric coronavirus that has been reported to infect a variety of animals and even humans. Cell-cell fusion has been identified as an alternative pathway for the cell-to-cell transmission of certain viruses, but the ability of PDCoV to exploit this transmission model, and the relevant mechanisms, have not been fully elucidated. Herein, we provide evidence that cell-to-cell transmission is the main mechanism supporting PDCoV spread in cell culture and that this efficient spread model is mediated by spike glycoprotein-driven cell-cell fusion. We found that PDCoV efficiently spread to non-susceptible cells via cell-to-cell transmission, and demonstrated that functional receptor porcine aminopeptidase N and cathepsins in endosomes are involved in the cell-to-cell transmission of PDCoV. Most importantly, compared with non-cell-to-cell infection, the cell-to-cell transmission of PDCoV was resistant to neutralizing antibodies and immune sera that potently neutralized free viruses. Taken together, our study revealed key characteristics of the cell-to-cell transmission of PDCoV and provided new insights into the mechanism of PDCoV infection.
Topics: Humans; Animals; Swine; Deltacoronavirus; Coronavirus; Antibodies, Neutralizing; Coronavirus Infections; Swine Diseases
PubMed: 37125733
DOI: 10.1080/22221751.2023.2207688 -
Viruses Sep 2023Emerging and re-emerging swine coronaviruses (CoVs), including porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea... (Review)
Review
Emerging and re-emerging swine coronaviruses (CoVs), including porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome-CoV (SADS-CoV), cause severe diarrhea in neonatal piglets, and CoV infection is associated with significant economic losses for the swine industry worldwide. Reverse genetics systems realize the manipulation of RNA virus genome and facilitate the development of new vaccines. Thus far, five reverse genetics approaches have been successfully applied to engineer the swine CoV genome: targeted RNA recombination, in vitro ligation, bacterial artificial chromosome-based ligation, vaccinia virus -based recombination, and yeast-based method. This review summarizes the advantages and limitations of these approaches; it also discusses the latest research progress in terms of their use for virus-related pathogenesis elucidation, vaccine candidate development, antiviral drug screening, and virus replication mechanism determination.
Topics: Animals; Swine; Coronavirus; Reverse Genetics; Coronavirus Infections; Porcine epidemic diarrhea virus; RNA; Diarrhea; Swine Diseases
PubMed: 37896780
DOI: 10.3390/v15102003 -
Viruses Jul 2023Porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), members of the genus Coronavirus, mainly cause acute diarrhea, vomiting and dehydration in...
Porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), members of the genus Coronavirus, mainly cause acute diarrhea, vomiting and dehydration in piglets, and thus lead to serious economic losses. In this study, we investigated the effects of nicotinamide (NAM) on PEDV and PDCoV replication and found that NAM treatment significantly inhibited PEDV and PDCoV reproduction. Moreover, NAM plays an important role in replication processes. NAM primarily inhibited PEDV and PDCoV RNA and protein synthesis rather than other processes. Furthermore, we discovered that NAM treatment likely inhibits the replication of PEDV and PDCoV by downregulating the expression of transcription factors through activation of the ERK1/2/MAPK pathway. Overall, this study is the first to suggest that NAM might be not only an important antiviral factor for swine intestinal coronavirus, but also a potential candidate to be evaluated in the context of other human and animal coronaviruses.
Topics: Animals; Humans; Swine; Porcine epidemic diarrhea virus; Niacinamide; Coronavirus; Deltacoronavirus; Coronavirus Infections; Diarrhea; Swine Diseases; Virus Replication
PubMed: 37515276
DOI: 10.3390/v15071591 -
PLoS Pathogens Oct 2023Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans, imposing great...
Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans, imposing great threats to the public safety and animal health. Porcine deltacoronavirus (PDCoV), a newly emerging enteropathogenic coronavirus, causes severe diarrhea in suckling piglets all over the world and poses potential risks of cross-species transmission. Here, we use PDCoV as a model of CoVs to illustrate the reciprocal regulation between CoVs infection and host antiviral responses. In this study, downregulation of DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed in PDCoV infected IPEC-J2 cells by isobaric tags for relative and absolute quantification (iTRAQ) and Western blotting analysis. Overexpression of POLDIP3 inhibits PDCoV infection, whereas POLDIP3 knockout (POLDIP3-/-) by CRISPR-Cas9 editing significantly promotes PDCoV infection, indicating POLDIP3 as a novel antiviral regulator against PDCoV infection. Surprisingly, an antagonistic strategy was revealed that PDCoV encoded nonstructural protein 5 (nsp5) was responsible for POLDIP3 reduction via its 3C-like protease cleavage of POLDIP3 at the glutamine acid 176 (Q176), facilitating PDCoV infection due to the loss of antiviral effects of the cleaved fragments. Consistent with the obtained data in IPEC-J2 cell model in vitro, POLDIP3 reduction by cleavage was also corroborated in PDCoV infected-SPF piglets in vivo. Collectively, we unveiled a new antagonistic strategy evolved by PDCoV to counteract antiviral innate immunity by nsp5-mediated POLDIP3 cleavage, eventually ensuring productive virus replication. Importantly, we further demonstrated that nsp5s from PEDV and TGEV harbor the conserved function to cleave porcine POLDIP3 at the Q176 to despair POLDIP3-mediated antiviral effects. In addition, nsp5 from SARS-CoV-2 also cleaves human POLDIP3. Therefore, we speculate that coronaviruses employ similar POLDIP3 cleavage mechanisms mediated by nsp5 to antagonize the host antiviral responses to sustain efficient virus infection.
Topics: Animals; Humans; Swine; Immunity, Innate; Virus Replication; Antiviral Agents; Coronavirus Infections; Swine Diseases; RNA-Binding Proteins
PubMed: 37801439
DOI: 10.1371/journal.ppat.1011702 -
Journal of Virology Oct 2023Retrograde transport has been reported to be closely associated with normal cellular biological processes and viral replication. As an emerging enteropathogenic...
Retrograde transport has been reported to be closely associated with normal cellular biological processes and viral replication. As an emerging enteropathogenic coronavirus with zoonotic potential, porcine deltacoronavirus (PDCoV) has attracted considerable attention. However, whether retrograde transport is associated with PDCoV infection remains unclear. Our present study demonstrates that retromer protein VPS35 acts as a critical host factor that is required for PDCoV infection. Mechanically, VPS35 interacts with PDCoV NS6, mediating the retrograde transport of NS6 from endosomes to the Golgi and preventing it from lysosomal degradation. Recombinant PDCoVs with an NS6 deletion display resistance to VPS35 deficiency. Our work reveals a novel evasion mechanism of PDCoV that involves the manipulation of the retrograde transport pathway by VPS35, providing new insight into the mechanism of PDCoV infection.
Topics: Animals; Coronavirus; Coronavirus Infections; Deltacoronavirus; Swine; Swine Diseases; Virus Replication; Viral Regulatory and Accessory Proteins; Vesicular Transport Proteins
PubMed: 37815351
DOI: 10.1128/jvi.00957-23 -
Vaccines Dec 2023Swine enteric coronaviruses (SECs) cause significant economic losses to the pig industry in China. Although many commercialized vaccines against transmissible... (Review)
Review
Swine enteric coronaviruses (SECs) cause significant economic losses to the pig industry in China. Although many commercialized vaccines against transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) are available, viruses are still widespread. The recent emergence of porcine deltacoronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV), for which no vaccines are available, increases the disease burden. In this review, we first introduced the genomic organization and epidemiology of SECs in China. Then, we discussed the current vaccine development and application in China, aiming to provide suggestions for better prevention and control of SECs in China and other countries.
PubMed: 38276670
DOI: 10.3390/vaccines12010011 -
Journal of Virology Nov 2023As a member of the δ-coronavirus family, porcine deltacoronavirus (PDCoV) is a vital reason for diarrhea in piglets, which can contribute to high morbidity and...
As a member of the δ-coronavirus family, porcine deltacoronavirus (PDCoV) is a vital reason for diarrhea in piglets, which can contribute to high morbidity and mortality rates. Initially identified in Hong Kong in 2012, the virus has rapidly spread worldwide. During PDCoV infection, the virus employs evasion mechanisms to evade host surveillance, while the host mounts corresponding responses to impede viral replication. Our research has revealed that PDCoV infection down-regulates the expression of PGAM5 to promote virus replication. In contrast, PGAM5 degrades PDCoV N through autophagy by interacting with the cargo receptor P62 and the E3 ubiquitination ligase STUB1. Additionally, PGAM5 interacts with MyD88 and TRAF3 to activate the IFN signal pathway, resulting in the inhibition of viral replication.
Topics: Animals; Coronavirus Infections; Interferon Type I; Signal Transduction; Swine; Swine Diseases; Ubiquitin-Protein Ligases; Virus Replication; Coronavirus Nucleocapsid Proteins; Deltacoronavirus; Phosphoprotein Phosphatases; Mitochondrial Proteins; Down-Regulation; Immune Evasion; RNA-Binding Proteins; Proteolysis
PubMed: 37882521
DOI: 10.1128/jvi.01470-23 -
Animals : An Open Access Journal From... Dec 2023are one of the most diverse mammal orders. They are considered reservoirs of main human pathogens, where coronaviruses (CoVs) and paramyxoviruses (PMVs) may be... (Review)
Review
are one of the most diverse mammal orders. They are considered reservoirs of main human pathogens, where coronaviruses (CoVs) and paramyxoviruses (PMVs) may be highlighted. Moreover, the growing number of publications on CoVs and PMVs in wildlife reinforces the scientific community's interest in eco-vigilance, especially because of the emergence of important human pathogens such as the SARS-CoV-2 and Nipha viruses. Considering that Brazil presents continental dimensions, is biologically rich containing one of the most diverse continental biotas and presents a rich biodiversity of animals classified in the order , the mapping of CoV and PMV genetics related to human pathogens is important and the aim of the present work. CoVs can be classified into four genera: , , and . Delta- and gammacoronaviruses infect mainly birds, while alpha- and betacoronaviruses contain important animal and human pathogens. Almost 60% of alpha- and betacoronaviruses are related to bats, which are considered natural hosts of these viral genera members. The studies on CoV presence in bats from Brazil have mainly assayed phyllostomid, molossid and vespertilionid bats in the South, Southeast and North territories. Despite Brazil not hosting rhinophilid or pteropodid bats, which are natural reservoirs of SARS-related CoVs and henipaviruses, respectively, CoVs and PMVs reported in Brazilian bats are genetically closely related to some human pathogens. Most works performed with Brazilian bats reported alpha-CoVs that were closely related to other bat-CoVs, despite a few reports of beta-CoVs grouped in the and subgenera. The family Paramyxoviridae includes four subfamilies (, , and ), and bats are significant drivers of PMV cross-species viral transmission. Additionally, the studies that have evaluated PMV presence in Brazilian bats have mainly found sequences classified in the and genera that belong to the subfamily. Despite the increasing amount of research on Brazilian bats, studies analyzing these samples are still scarce. When surveying the representativeness of the CoVs and PMVs found and the available genomic sequences, it can be perceived that there may be gaps in the knowledge. The continuous monitoring of viral sequences that are closely related to human pathogens may be helpful in mapping and predicting future hotspots in the emergence of zoonotic agents.
PubMed: 38200819
DOI: 10.3390/ani14010088 -
Journal of Virology Jun 2023Goblet cells and their secreted mucus are important elements of the intestinal mucosal barrier, which allows host cells to resist invasion by intestinal pathogens....
Porcine Deltacoronavirus Infection Disrupts the Intestinal Mucosal Barrier and Inhibits Intestinal Stem Cell Differentiation to Goblet Cells via the Notch Signaling Pathway.
Goblet cells and their secreted mucus are important elements of the intestinal mucosal barrier, which allows host cells to resist invasion by intestinal pathogens. Porcine deltacoronavirus (PDCoV) is an emerging swine enteric virus that causes severe diarrhea in pigs and causes large economic losses to pork producers worldwide. To date, the molecular mechanisms by which PDCoV regulates the function and differentiation of goblet cells and disrupts the intestinal mucosal barrier remain to be determined. Here, we report that in newborn piglets, PDCoV infection disrupts the intestinal barrier: specifically, there is intestinal villus atrophy, crypt depth increases, and tight junctions are disrupted. There is also a significant reduction in the number of goblet cells and the expression of . , using intestinal monolayer organoids, we found that PDCoV infection activates the Notch signaling pathway, resulting in upregulated expression of and downregulated expression of and thereby inhibiting the differentiation of intestinal stem cells into goblet cells. Our study shows that PDCoV infection activates the Notch signaling pathway to inhibit the differentiation of goblet cells and their mucus secretion, resulting in disruption of the intestinal mucosal barrier. The intestinal mucosal barrier, mainly secreted by the intestinal goblet cells, is a crucial first line of defense against pathogenic microorganisms. PDCoV regulates the function and differentiation of goblet cells, thereby disrupting the mucosal barrier; however, the mechanism by which PDCoV disrupts the barrier is not known. Here, we report that , PDCoV infection decreases villus length, increases crypt depth, and disrupts tight junctions. Moreover, PDCoV activates the Notch signaling pathway, inhibiting goblet cell differentiation and mucus secretion and . Thus, our results provide a novel insight into the mechanism underlying intestinal mucosal barrier dysfunction caused by coronavirus infection.
Topics: Animals; Coronavirus; Coronavirus Infections; Goblet Cells; Signal Transduction; Swine; Swine Diseases; Stem Cells; Cell Differentiation; Receptors, Notch
PubMed: 37289083
DOI: 10.1128/jvi.00689-23