Search Results (593)

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article

The midgut of Antheraea pernyi plays a critical role in antiviral defense. However, its transcriptional complexity remains poorly understood. Here, a full-length (FL) transcriptome atlas of A. pernyi midgut was developed by integrating PacBio Iso-Seq and RNA-seq techniques. The transcriptome sequences included 1850 novel protein-coding genes, 17,736 novel alternative isoforms, 1664 novel long non-coding RNAs (lncRNAs), and 858 transcription factors (TFs). In addition, 2471 alternative splicing (AS) events and 3070 alternative polyadenylation (APA) sites were identified. Moreover, 3426 and 4796 differentially expressed genes (DEGs) and isoforms were identified after ApNPV infection, respectively, besides the differentially expressed lncRNAs (164), TFs (171), and novel isoforms of ApRelish (1) and ApSOCS2 (4). Enrichment analyses showed that KEGG pathways related to metabolism were suppressed, whereas GO terms related to DNA synthesis and replication were induced. Furthermore, the autophagy and apoptosis pathways were significantly enriched among the upregulated genes. Protein–protein interaction network (PPI) analysis revealed the coordinated downregulation of genes involved in mitochondrial ribosomes, V-type and F-type ATPases, and oxidative phosphorylation, indicating the disruption of host energy metabolism and organelle acidification. Moreover, coordinated upregulation of genes associated with cytoplasmic ribosomes was observed, suggesting that the infection by ApNPV interferes with host translational machinery. These results show that ApNPV infection reprograms energy metabolism, biosynthetic processes, and immune response in A. pernyi midgut. Our study provides a foundation for elucidating the mechanisms of A. pernyi–virus interactions, particularly how the viruses affect host defense strategies. Full article

Viral oncolysis is considered a promising cancer treatment method because of its good tolerability and durable anti-tumor effects. Compared with other oncolytic viruses, Newcastle disease virus (NDV) has some distinct advantages. As an RNA virus, NDV does not recombine with the host genome, making it safer compared with DNA viruses and retroviruses; NDV can induce syncytium formation, allowing the virus to spread among cells without exposure to host neutralizing antibodies; and its genome adheres to the hexamer genetic code rule (genome length as a multiple of six nucleotides), ensuring accurate replication, low recombination rates, and high genetic stability. Although wild-type NDV has a killing effect on various tumor cells, its oncolytic effect and working mechanism are diverse, increasing the complexity of generating engineered oncolytic viruses with NDV. This study aims to employ whole-genome CRISPR-Cas9 knockout screening and RNA sequencing to identify putative key regulatory factors involved in the interaction between NDV and human colon cancer HCT116 cells and map their global interaction networks. The results suggests that NDV infection disrupts cellular homeostasis, thereby exerting oncolytic effects by inhibiting cell metabolism and proliferation. Meanwhile, the antiviral immune response triggered by NDV infection, along with the activation of anti-apoptotic signaling pathways, may be responsible for the limited oncolytic efficacy of NDV against HCT116 cells. These findings not only enhance our understanding of the oncolytic mechanism of NDV against colonic carcinoma but also provide potential strategies and targets for the development of NDV-based engineered oncolytic viruses. Full article

Human coronaviruses are a group of viruses that continue to threaten human health. In this study, we investigated the antiviral activity of 4-hydroxychalcone (4HCH), a chalcone derivative, against human coronavirus HCoV-OC43. We found that 4HCH significantly inhibited the cytopathic effect, reduced viral protein and RNA levels in infected cells, and increased the survival rate of HCoV-OC43-infected suckling mice. Mechanistically, 4HCH targets the early stages of viral infection by binding to the epidermal growth factor receptor (EGFR) and inhibiting the EGFR/AKT/ERK1/2 signaling pathway, thereby suppressing viral replication. Additionally, 4HCH significantly reduced the production of pro-inflammatory cytokines and chemokines in both HCoV-OC43-infected RD cells and a suckling mouse model. Our findings demonstrate that 4HCH exhibits potent antiviral activity both in vitro and in vivo, suggesting its potential as a therapeutic agent against human coronaviruses. This study highlights EGFR as a promising host target for antiviral drug development and positions 4HCH as a candidate for further investigation in the treatment of coronavirus infections. Full article

Coronaviruses, particularly those classified as highly pathogenic species, pose a significant threat to global health. These viruses hijack host cellular membranes and proteins to facilitate their replication, primarily through the formation of replication organelles (ROs). However, the precise regulatory mechanisms underlying RO formation remain poorly understood. To elucidate these mechanisms, we conducted mass spectrometry analyses, identifying interactions between the host protein DnaJ homolog subfamily C member 11 (DNAJC11) and the SARS-CoV-2 nonstructural protein 3 (NSP3) protein. Notably, results showed that DNAJC11 depletion reduces SARS-CoV-2 infection, indicating possible positive regulatory involvement. But the ectopic expression of DNAJC11 did not lead to marked alterations in immune or inflammatory responses. DNAJC11 enhanced NSP3 expression stability through endogenous apoptosis pathways and facilitated its interaction with NSP4, thereby promoting the formation of double-membrane vesicles (DMVs). Knockdown of DNAJC11 reduced DMV number and size, accompanied by dysregulation of the endoplasmic reticulum and mitochondria. However, supplementation with DNAJC11 restored both DMV number and size. These findings provide novel insights into the role of DNAJC11 as a host factor that modulates DMV formation and supports SARS-CoV-2 replication by targeting the NSP3 protein. This study advances our understanding of the molecular interactions between host and viral components and highlights DNAJC11 as a potential target for antiviral interventions. Full article

Kyasanur Forest disease virus (KFDV), a tick-borne Orthoflavivirus endemic to the Indian subcontinent, is a public health threat due to its recurrent outbreaks and expanding geographic range. This review provides a comprehensive overview of KFDV, encompassing its epidemiological trends, transmission dynamics, and ecological determinants that influence its spread. We delve into the current understanding of KFDV pathogenesis, highlighting key viral and host factors that drive infection and disease progression. Despite the absence of targeted antiviral therapies, recent advances have spurred the development of candidate therapeutics, including broad-spectrum antivirals and immunomodulators. We also discuss progress in vaccine development, with an emphasis on the limitations of the existing formalin-inactivated vaccine and the promise of next-generation platforms. Furthermore, we explore recent innovations in diagnostics, including molecular and serological tools, that aim to improve early detection and surveillance. A multidisciplinary approach integrating virology, immunology, ecology, and public health is essential for the effective management and eventual control of KFDV outbreaks. Full article

Alphaviruses engage a diverse array of attachment factors and receptors during viral entry, resulting in a broad host range and disease spectrum, and thus presenting them as a major global public health concern. The development of effective antivirals against these arboviruses relies on a comprehensive understanding of the molecular interplay between these viruses and host cell factors, as well as the wide range of immune responses that ensue following viral infection. In this review, we present the current understanding of the complex landscape of alphavirus interaction with attachment factors and entry receptors, some of which are characterized structurally, while others are characterized biochemically. Additionally, we provide an overview of the molecular bases of epitope recognition by neutralizing and non-neutralizing antibodies against alphaviruses, and how icosahedral symmetry influences these interactions, such as occupancy and neutralization potency. We further discuss the structural bases of epitope recognition of a few pan-alphavirus antibodies, their potential therapeutic implications, and offer future perspectives on the development of effective therapeutics against clinically relevant alphaviruses. Full article

Polyphenols are structurally diverse plant metabolites that have attracted significant interest. Their compositions are versatile, depending on their structures, including the number of rings in the polyphenol composition. Based on these attributes, polyphenols can be classified as flavanols, anthocyanins, flavones, phenolic acids, stilbenes, and lignans. Polyphenols mainly possess inhibition of viral replication, interference with viral protein synthesis, and modulation of immune responses, providing significant antiviral effects against several viruses, including herpes simplex virus, hepatitis C virus, and influenza. They are crucial for medical compounds in diverse, versatile treatments, namely in diabetes, cardiovascular disorders, cancer, and neurodegenerative problems. Plants are the primary source of bioactive molecules, which are valued for their anti-inflammatory, antioxidant, anticancer, and antiviral activities. Especially, polyphenols are extracted as the most abundant bioactive compounds of plants. Moreover, viral infections are one of the major factors in illnesses and diseases, along with bacteria and fungi. Numerous in vitro and in vivo studies report antiviral activity against SARS-CoV-2, Mayaro virus, dengue virus, herpesvirus, and influenza A virus, though clinical validation remains limited. Additionally, inhibition of viral entry, interference with viral replication, modulation of host immune response, and direct virucidal effects were examined. Full article

Background and aim: The COVID-19 pandemic, caused by SARS-CoV-2, remains a global health crisis despite vaccination efforts, necessitating novel therapeutic strategies. Natural compounds from Syzygium aromaticum (clove), such as eugenol and β-caryophyllene, exhibit antiviral and anti-inflammatory properties, while host genetic factors, including miR-21 rs1292037 polymorphism, may influence disease susceptibility and severity. This study investigates the dual approach of targeting SARS-CoV-2 via Syzygium aromaticum phytoconstituents while assessing the role of miR-21 rs1292037 in COVID-19 pathogenesis. Methods: Firstly, molecular docking and molecular dynamics simulations were employed to assess the binding affinities of eugenol and caryophyllene against seven key SARS-CoV-2 proteins—including Spike-RBD, 3CLpro, and RdRp—using SwissDock (AutoDock Vina) and the Desmond software package, respectively. Secondly, GC-MS was used to characterize the composition of clove extract. Thirdly, pharmacokinetic profiles were predicted using in silico models. Finally, miR-21 rs1292037 genotyping was performed in 100 COVID-19 patients and 100 controls, with cytokine and coagulation markers analyzed. Results: Docking revealed strong binding of eugenol to viral Envelope Protein (−5.267 kcal/mol) and caryophyllene to RdRp (−6.200 kcal/mol). ADMET profiling indicated favorable absorption and low toxicity. Molecular dynamics simulations confirmed stable binding of methyl eugenol and caryophyllene to SARS-CoV-2 proteins, with caryophyllene–7Z4S showing the highest structural stability, highlighting its strong antiviral potential. Genotyping identified the TC genotype as prevalent in patients (52%), correlating with elevated IL-6 and D-dimer levels (p ≤ 0.01), suggesting a hyperinflammatory phenotype. Males exhibited higher ferritin and D-dimer (p < 0.0001), underscoring sex-based disparities. Conclusion: The bioactive constituents of Syzygium aromaticum exhibit strong potential as multi-target antivirals, with molecular simulations highlighting caryophyllene’s particularly stable interaction with the 7Z4S protein. Methyl eugenol also maintained consistent binding across several SARS-CoV-2 targets. Additionally, the miR-21 rs1292037 polymorphism may influence COVID-19 severity through its role in inflammatory regulation. Together, these results support the combined application of phytochemicals and genetic insights in antiviral research, pending further clinical verification. Full article

Beta-sitosterol (BS), a naturally occurring phytosterol abundant in plants, has been reported to exhibit diverse biological activities, including immunomodulatory and antiviral effects. Classical swine fever virus (CSFV), a member of the Pestivirus genus, remains a persistent threat to the swine industry worldwide, causing considerable economic damage. Our research found that BS significantly enhances the replication of both the CSFV-Shimen strain and the attenuated C-strain vaccine virus in PK-15 cells. Additionally, transcriptomic profiling (RNA-Seq) identified 175 differentially expressed genes (DEGs) following BS exposure, comprising 53 upregulated and 122 downregulated genes. Further results demonstrated that treatment with β-sitosterol suppressed IκBα expression, thereby activating the NF-κB pathway, and that knockdown of endogenous IκBα significantly promoted CSFV replication. These findings contribute to a deeper understanding of how BS influences the CSFV infection process, suggesting its role as a host lipid-associated factor facilitating viral propagation. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have been shown to inhibit SARS-CoV-2 replication and are approved for treating SARS-CoV-2 infections. Nirmatrelvir inhibits the viral main protease (M^pro), a key enzyme for processing polyproteins in viral replication. In contrast, molnupiravir, favipiravir, and remdesivir are prodrugs that target RNA-dependent RNA polymerase (RdRp), which is crucial for genome replication and subgenomic RNA production. However, undergoing extensive metabolism profoundly impacts their therapeutic effects. Carboxylesterases (CES) are a family of enzymes that play an essential role in the metabolism of many drugs, especially prodrugs that require activation through hydrolysis. Molnupiravir is activated by carboxylesterase-2 (CES2), while remdesivir is hydrolytically activated by CES1 but inhibits CES2. Nirmatrelvir and remdesivir are oxidized by the same cytochrome P450 (CYP) enzyme. Additionally, various transporters are involved in the uptake or efflux of these drugs and/or their metabolites. It is well established that drug-metabolizing enzymes and transporters are differentially expressed depending on the cell type, and these genes exhibit significant polymorphisms. In this review, we examine how CES-related cellular and genetic factors influence the therapeutic activities of these widely used COVID-19 medications. This article highlights implications for improving product design, targeted inhibition, and personalized medicine by exploring genetic variations and their impact on drug metabolism and efficacy. Full article

This study explores the viral dynamics of SARS-CoV-2 infection within host cells by incorporating the pharmacological effects of andrographolide—a bioactive compound extracted from Andrographis paniculata, renowned for its antiviral, anti-inflammatory, and immunomodulatory properties. Through the application of mathematical modeling, the interactions among the virus, host cells, and immune responses are simulated to provide a comprehensive analysis of viral behavior over time. Two distinct models were employed to assess the impact of varying andrographolide dosages on viral load, target cell populations, and immune responses. One model revealed a clear dose–response relationship, whereas the other indicated that additional biological or pharmacological factors may modulate drug efficacy. Both models demonstrated stability, with basic reproductive numbers (R₀) suggesting the potential for viral propagation in the absence of effective therapeutic interventions. This study emphasizes the significance of understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of andrographolide to optimize its therapeutic potential. The findings also underscore the necessity for further investigation into the compound’s absorption, distribution, metabolism, and excretion (ADME) characteristics, as well as its prospective applications in the treatment of not only COVID-19 but also other viral infections. Overall, the results lay a foundational framework for future experimental research and clinical trials aimed at refining andrographolide dosing regimens and improving patient outcomes. Full article

PLA2G16 is a member of the phospholipase A2 family that catalyzes the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. Previously, PLA2G16 was found to be a host factor for picornaviruses. Here, we discovered that the Foot-and-Mouth Disease Virus (FMDV) infection led to an elevation in PLA2G16 transcription. We established PLA2G16 overexpression and knockdown cell lines in PK-15 cells to investigate the potential role of PLA2G16 in FMDV infection. Our findings revealed that during FMDV infection, PLA2G16-overexpressing cells had increased levels of phosphorylated STAT1 and the interferon-stimulating factors ISG15 and ISG56. In PLA2G16-overexpressing cells, p-STAT1 was observed at higher levels and earlier than in wild-type cells. Subsequent research demonstrated that PLA2G16 specifically promoted an antiviral innate immune response against FMDV. The host could detect the early release of FMDV viral nucleic acid in PLA2G16-overexpressing cells and trigger the interferon signaling pathway. Additionally, we discovered that the supernatants of PLA2G16-overexpressing cells stimulated the production of higher levels of ISG56 and phosphorylated STAT1. This suggests that PLA2G16-overexpressing cells can activate the innate immune pathway of uninfected cells after FMDV infection. Full article

Previously, we developed a porcine bronchial epithelial cell line designated as PBE cells and demonstrated that this cell line possesses functional Toll-like receptor 3 (TLR3), triggering the expressions of interferons (IFNs), antiviral factors, and inflammatory cytokines after its stimulation with the synthetic double-stranded ARN poly(I:C). In this work, we aimed to further characterize the PBE cell line as a reliable in vitro model for investigating swine influenza virus (SIV) infection and immunity. We evaluated the capacity of two SIV subtypes, H1N1 and H3N2, to replicate and induce cytopathic effects in PBE cells and to modulate the expressions of IFNs, antiviral factors, inflammatory cytokines, and negative regulators of the TLR signaling. We demonstrated that PBE cells are susceptible to both H1N1 and H3N2. SIV infected PBE cells inducing notable cytopathic effects as shown by the alteration of transepithelial electrical resistance (TEER) and cilia. Both SIV subtypes replicated in PBE cells in similar proportion and altered TEER values in comparable magnitudes. However, SIV H3N2 induced higher alterations of cilia than H1N1. SIV infection induced changes in all the immune factors evaluated in PBE cells. We detected quantitative differences when the subtypes H1N1 and H3N2 were compared. The fold expression changes of IFN-β, Mx1, Mx2, IFITM1, OAS1, OAS2, and OASL were higher in PBE cells infected with H3N2 than in cells challenged with H1N1. In addition, although both subtypes stimulated IL-8 expression, only the H3N2 induced IL-6 in infected PBE cells. SIV H1N1 and H3N2 also upregulated the expressions of the negative regulators A20, BCL-3, and MKP-1, while only H1N1 increased SIGIRR and Tollip. Immortalized respiratory cell lines from pigs can be useful in vitro systems for the study of viral infections and immune responses. These studies are of importance in the context of influenza infections not only for the agricultural field because pigs are natural hosts of these viruses but also because these animals serve as intermediate reservoirs of viruses that can threaten humans’ health. We demonstrated here that the PBE cell line can be a useful in vitro model to study SIV infection and immunity. Full article

Background/Objectives: Enterovirus-D68 (EV-D68) and rhinoviruses are major contributors to respiratory illnesses in children, presenting a spectrum of clinical manifestations ranging from asymptomatic cases to severe lower respiratory tract infections. No specific antiviral treatments are currently approved for these viruses. Method: We conducted a comprehensive literature review of antiviral agents investigated for EV-D68 and rhinovirus infections. Results: Several antiviral candidates are under investigation, each targeting distinct stages of the viral replicative cycle. Capsid-binding agents and monoclonal antibodies prevent viral attachment by blocking receptor-virus interactions. Inhibitors of viral replication proteins disrupt polyprotein processing and replication organelle biogenesis by targeting non-structural viral proteins. Host factor inhibitors impair viral attachment, replication organelle formation, or RNA replication by interfering with critical host pathways. Conclusions: While no specific antivirals are yet approved for EV-D68 and rhinovirus infections, emerging therapeutic candidates offer potential avenues for treatment. Continued preclinical and clinical investigation will be essential to validate these approaches and expand the available options for affected patients. Full article