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Porcine circovirus type 2 (PCV2), porcine circovirus type 3 (PCV3), and pseudorabies virus (PRV) are major pathogens posing significant threats to the swine industry. Viral evolution and mutations have limited the efficacy of current commercial vaccines, necessitating the development of more effective prophylactic strategies. In this study, a novel recombinant virus strain, designated as rPRV-ΔTK-PCV3(Cap)/ΔgIgE-PCV2(Cap), was generated using PRV SX-10 variant as the backbone. CRISPR/Cas9-mediated deletion of TK and gE/gI genes was performed, followed by insertion of PCV3 and PCV2 capsid protein genes into the respective loci. The engineered recombinant strain demonstrated stable proliferation in BHK-21 cells, efficiently expressed heterologous PCV3 and PCV2 capsid proteins, while maintaining biological properties comparable to its parental strain. The rPRV-ΔTK-PCV3(Cap)/ΔgIgE-PCV2(Cap) demonstrated favorable safety and immunogenicity profiles in mice and piglets, eliciting robust immune responses characterized by high titers of specific antibodies against PRV, PCV3, and PCV2, along with significantly elevated levels of cytokines (IFN-γ, IL-2, and IL-4). Histopathological analysis and viral load quantification demonstrated that rPRV-ΔTK-PCV3(Cap)/ΔgIgE-PCV2(Cap) immunization significantly attenuated tissue lesions and decreased viral copies of PRV and PCV in mice and piglets. Collectively, these findings suggest that rPRV-ΔTK-PCV3(Cap)/ΔgIgE-PCV2(Cap) serves as a promising candidate vaccine against PRV and PCV infections. •Generated novel recombinant virus rPRV-ΔTK-PCV3(Cap)/ΔgIgE-PCV2(Cap) via CRISPR/Cas9.•Demonstrated stable virus proliferation and efficient PCV3/PCV2 capsid protein expression.•Induced robust immune responses against PRV, PCV3, and PCV2.•Provided valuable insights for the development of trivalent vaccine candidates.

This study was aimed to investigate the frequency of PiCV recombination, the kinetics of PiCV viremia and shedding and the correlation between viral replication and host immune response in young pigeons subclinically infected with various PiCV variants and kept under conditions mimicking the OLR system. Fifteen racing pigeons originating from five breeding facilities were housed together for six weeks. Blood and cloacal swab samples were collected from birds every seven days to recover complete PiCV genomes and determine PiCV genetic diversity and recombination dynamics, as well as to assess virus shedding rate, level of viremia, expression of selected genes and level of anti-PiCV antibodies. Three hundred and eighty-eight complete PiCV genomes were obtained and thirteen genotypes were distinguished. Twenty-five recombination events were detected. Recombinants emerged during the first three weeks of the experiment which was consistent with the peak level of viremia and viral shedding. A further decrease in viremia and shedding partially corresponded with IFN-γ and MX1 gene expression and antibody dynamics. Considering the role of OLR pigeon rearing system in spreading infectious agents and allowing their recombination, it would be reasonable to reflect on the relevance of pigeon racing from both an animal welfare and epidemiological perspective.

Porcine circovirus 2 (PCV2) is an economically significant, ubiquitous pathogen affecting the global swine industry. While vaccines have been highly efficacious in controlling clinical disease, questions have arisen in recent years regarding gaps in clinical protection observed in the field due to heterologous PCV2 infection and coinfections with virulent, contemporary porcine reproductive and respiratory syndrome virus (PRRSV) isolates. Therefore, this study evaluated clinical, pathological, and immunological differences in homologous and heterologous PCV2 vaccinated pigs co-challenged with PCV2d and PRRSV. The study closely mimicked field conditions where 21-day-old commercial pigs were vaccinated with a commercial PRRSV vaccine and either a commercial PCV2a or PCV2d vaccine or left as PCV2 unvaccinated controls. Pigs were co-challenged with PCV2d and PRRSV restriction fragment polymorphism (RFLP) 1–7-4 28 days post-vaccination. In addition to significantly higher mortality, the unvaccinated group had significantly higher tissue viral load and viremia in addition to moderate to severe lymphoid depletion with significantly greater PCV2 antigen detected in the lymph nodes, tonsil, and lung compared to both vaccinated groups. While PCV2 vaccination regardless of subtype prevented the development of severe clinical PCVAD in the majority of vaccinates, the PCV2d vaccinates had reduced tissue viral load, significantly lower viremia, and reduced lymphoid depletion with less PCV2 antigen detected in tissues compared to the PCV2a vaccinates. Additionally, approximately 20 % of the PCV2a vaccinates had moderate to severe lymphoid depletion with moderate to severe antigen detection, which is associated with clinical PCVAD. While total levels of PCV2-specific antibodies measured by ELISA were similar between the PCV2a and PCV2d vaccinates, PCV1–2 chimeric virus neutralization assays revealed differential subtype-specific neutralizing antibody (NA) titers among the PCV2a and PCV2d vaccinates. Prior to challenge on day 28 (28 days post-vaccination), PCV2d vaccinates had significantly higher NA titers against the PCV1–2d vaccine and challenge chimeric viruses, while the PCV2a vaccinates had significantly higher NA titers against the PCV1–2a vaccine chimeric virus. Collectively, homologous vaccination may provide greater protection in virulent co-infection scenarios in the field. This study provides further insight into differences in protection elicited by homologous and heterologous vaccination, resulting in valuable insights to enhance PCV2 control strategies in the current PCV2d/PRRSV co-infection paradigm. •Severe PCVAD and increased mortality were observed in non-vaccinated pigs after PCV2d/PRRSV co-challenge.•PCV2d vaccinates showed reduced viral load, viremia, and minimal lymphoid depletion compared to PCV2a vaccinates.•PCV2d vaccinates had higher neutralizing antibody titers against PCV2d, while PCV2a vaccinates showed delayed antibody responses.•A subset of PCV2a vaccinates developed moderate lymphoid depletion and PCVAD-compatible lesions.•Both vaccines reduced clinical signs but did not prevent PCV2 detection in tissues, highlighting the need for improved vaccine strategies.

Porcine circoviruses (PCVs) have been a significant concern in swine health, with PCV2 being a well‐established pathogen. However, the newly discovered PCV3 and PCV4 have emerged, and their impact on piglets remains less understood. Understanding their pathogenicity is crucial for effective porcine health management. In this study, 3‐week‐old piglets were inoculated with PCV2, PCV3, and PCV4. PCV2 led to expected growth inhibition and severe clinical signs like anorexia. PCV3, though showing milder symptoms, exhibited unique tissue tropism, with detectable virus in the heart, lungs, and brain tissues. PCV4 caused distinct tissue damage, including cardiac fibrosis and renal changes. In terms of immune responses, each virus triggered different cytokine profiles. PCV3 and PCV4 also demonstrated replication capabilities in vitro and in vivo. PCV3 and PCV4 clearly have pathogenic patterns that differ from those of PCV2. These findings provide essential insights for veterinarians and swine producers. Understanding these viruses’ behavior aids in developing targeted prevention and control strategies, such as improved diagnostic tools and potential new vaccines, to enhance porcine health management and safeguard the swine industry from the threats posed by these emerging PCVs.

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus (PCVs) are two major viruses that affect pigs. Coinfections between PRRSV and PCV2 are frequently reported in most outbreaks, with clinical presentations involving dyspnea, fever, reduced feed intake, weight loss, and death in fattening pigs. The NADC30-like PRRSV and PCV2d are the main circulating virus strains found in China. This study determines the impact of NADC30-like PRRSV and PCV2d mono-infection and coinfection on the immune system, organ pathology, and viral shedding in five-week-old post-weaned pigs. Pigs were randomly divided into six groups: PBS, PRRSV, PCV2, PRRSV-PCV2 coinfection (co), and PRRSV-PCV2 or PCV2-PRRSV sequential infections. Fever, dyspnea, decreased feed intake, weight loss, and pig deaths occurred in groups infected with PRRSV, Co-PRRSV-PCV2, and PRRSV-PCV2. The viral load was higher in Co-PRRSV-PCV2, PRRSV-PCV2, and PCV2-PRRSV than those mono-infected with PRRSV or PCV2. Additionally, cytokines (IFN-γ, TNF-α, IL-4, and IL-10) produced by pigs under Co-PRRSV-PCV2 and PRRSV-PCV2 groups were more intense than the other groups. Necropsy findings showed hemorrhage, emphysema, and pulmonary adhesions in the lungs of pigs infected with PRRSV. Smaller alveoli and widened lung interstitium were found in the Co-PRRSV-PCV2 and PRRSV-PCV2 groups. In conclusion, PRRSV and PCV2 coinfection and sequential infection significantly increased viral pathogenicity and cytokine responses, resulting in severe clinical signs, lung pathology, and death.

Cyclic GMP-AMP synthase (cGAS) is a key sensor of double-stranded DNA (dsDNA), initiating oligomerization and phase separation to drive immune responses against pathogens and endogenous damage. Porcine circovirus (PCV) induces immunosuppression, heightening susceptibility to secondary infections, but the underlying mechanisms remain unclear. Here, we report PCV type 2d (PCV2d) infection fails to induce type I interferons (IFN-I) and significantly suppresses IFN-I production upon poly (dA:dT) stimulation in a dose-dependent manner. Mechanistically, the replication-related protein (Rep) proteins of PCV2, PCV3 and PCV4 inhibit cGAS-mediated IFN-I induction by competitively binding dsDNA, thereby disrupting cGAS oligomerization and phase separation. Interestingly, Rep also suppresses mitochondria DNA-induced cGAS activation. We further identify Rep residues Q12 and R199-W202 as key regions facilitating dsDNA binding. Our findings reveal a previously unrecognized mechanism by which circovirus Rep antagonizes cGAS activation, providing new insights into PCV-induced immunosuppression.

Coinfections with porcine circovirus types 2, 3, and 4 (PCV2, PCV3, and PCV4) are increasingly being detected in the swine industry. However, there is no commercially available vaccine which prevents coinfection with PCV2, PCV3, and PCV4. The development of a vaccine expressing capsid (Cap) fusion proteins of multiple PCVs represents a promising approach for broadly preventing infection with PCVs. In this study, we developed a PCV subunit vaccine candidate (Cap 2-3-4) by predicting, screening, and fusing antigenic epitopes of Cap proteins of PCV2, PCV3, and PCV4. Immunoprotection assays showed that the prokaryotic expression of Cap 2-3-4 could effectively induce high levels of PCV2, PCV3, and PCV4 Cap-specific antibodies and successfully neutralize both PCV2 and PCV3. Furthermore, Cap 2-3-4 demonstrated a potent ability to activate cellular immunity and thus prevent lung damage in mice. This study provides a new option for the development of broad vaccines against PCVs.

Porcine circovirus type 2 (PCV2) infection can cause immunosuppression-related diseases in pigs. Currently, it is still recognized as an important infectious pathogen of the swine industry in the world. In this study, we discovered that PCV2 infection disrupted the Th1/Th2/Th17/Treg immune equilibrium, and the differentiation capacity of Treg cells increased significantly. Briefly, PCV2 infection promoted the secretion of cytokine TGF-β, recruited Smad3, and phosphorylated it. Subsequently, the phosphorylated Smad3 transmitted the signal from the cell membrane to the nucleus and bound to the enhancer of Foxp3, thereby enhancing the transcription level of Foxp3 and facilitating the differentiation of Treg cells. This study enriches the pathogenic mechanism of PCV2 persistent infection and provided a theoretical basis for the prevention and control of immunosuppressive diseases.

Porcine circovirus type 2 (PCV2) is a significant pathogen in swine, exhibiting notable genetic and phenotypic diversity. This study explores the evolutionary mechanisms influencing PCV2 variability, emphasizing the role of viral features and host environment. An extensive collection of globally available ORF2 sequences of the main PCV2 genotypes (i.e., PCV2a, PCV2b, and PCV2d) sampled from wild boars and domestic pigs was analyzed, using a combination of phylodynamic approaches and biostatistical methods to infer the presence and patterns of selective pressures in different virus population subsets. Significant differences were observed between strains collected from domestic and wild populations, with the former appearing to be under stronger selective pressures at specific capsid positions. These pressures are likely driven by immune-mediated selection acting on critical residues for immune system recognition and evasion. A comprehensive evaluation of substitution patterns also revealed a trend toward maintaining or enhancing amino acid polarity, with neutral residues often replaced by polar or charged ones. This shift may influence the virus interaction with host proteins, particularly glycosaminoglycans such as heparan sulfate-like molecules. The observed variability among hosts and genotypes highlights both the importance of host environment as a key driver of viral evolution and the plasticity of PCV2 adaptability, with multiple alternative evolutionary pathways seemingly being selected. The findings underscore the complex evolutionary trajectories followed by PCV2 on a global scale and suggest that the intensification of pig farming and associated management practices may have significantly shaped PCV2 evolution, contributing to the current epidemiological landscape.

Oxidative stress plays an important role in the pathogenesis of virus infection and antioxidants are becoming promising candidates as therapeutic agents. This study is designed to investigate the effect of total flavonoids of Spatholobus suberectus Dunn (TFSD) on oxidative stress in mice induced by porcine circovirus type 2 (PCV2) infection. The PCV2 infection leads to significant decrease in thymus and spleen indices, elevation of xanthine oxidase (XOD) and myeloperoxidase (MPO) activities, reduction in GSH level and GSH to GSSG ratio and decline of superoxide dismutase (SOD) activity, indicating the formation of immunosuppression and oxidative stress. TFSD treatment recovered the alteration of viscera index, antioxidant content and activities of oxidative-associated enzymes to a level similar to control. Our findings suggested that PCV2 induced immunosuppression and oxidative stress in mice and TFSD might be able to protect animals from virus infection via regulation of immune function and inhibition of oxidative stress.