ObjectivesThis study aims to develop DABPU-DM derivatives that inhibit host adipose triglyceride lipase (ATGL) and identify the one with the highest broad-spectrum anti-coronaviral efficacy.MethodsThe antiviral effectiveness of DABPU-DM derivatives against representative viruses from all four genera within the subfamily Orthocoronavirinae was assessed using western blot, RT-qPCR, and immunofluorescence assay (IFA). The reduction in free fatty acid (FFA) and free glycerol (FG) levels following ATGL inhibition was measured with FFA and FG quantification assays. The antiviral effect of DABPU-DE with remdesivir against SARS-CoV-2, either alone or in combination, was evaluated by IFA, and their synergistic effect was analyzed using SynergyFinder 3.0.ResultsAmong six ATGL inhibitors, DABPU-DE exhibited the highest antiviral activity and safety, yielding a more favorable selectivity index than the other compounds. The enhanced antiviral effectiveness of DABPU-DE was linked to its diethylurea group, which increases ATGL binding affinity by enhancing hydrophobic and hydrogen-bonding interactions. In contrast, the weakest antiviral effect was observed with DABPU-DPh because its bulky diphenylurea group sterically hindered optimal binding and reduced interactions with ATGL. Additionally, combining DABPU-DE with remdesivir, which targets viral RNA-dependent RNA polymerase, produced strong, synergistic suppression of SARS-CoV-2 infection in Vero E6 cells.ConclusionOur findings indicate that the broad-spectrum anti-coronaviral activity of these compounds, particularly DABPU-DE, provides a promising preclinical foundation. This study underscores the potential of ATGL-targeted interventions as a viable strategy for managing current SARS-CoV-2 variants and preparing for future coronavirus outbreaks.

Background Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen of porcine reproductive and respiratory syndrome (PRRS) which is an important viral infectious disease. PRRSV is a positive-sense single-stranded RNA virus and causes serious economic losses to the pig industry worldwide. The oligoadenylate synthesis (OAS) /Ribonuclease L (RNase L) pathway plays a key role in host innate immune response to inhibit RNA virus infection. However, whether PRRSV proteins inhibit the activation of the OAS/RNase L pathway is less well understood. Results In this study, we first found that the nonstructural protein (Nsp) 11 could significantly decrease OAS1 and RNase L expression and inhibit poly (I: C)-mediated ribosomal RNA (rRNA) degradation and apoptosis by agarose gel electrophoresis and TUNEL assay, suggesting that Nsp11 decreased activation of the OAS/RNase L pathway. Western blotting showed that the PRRSV infection or Nsp11 overexpression reduced OAS1 and RNase L expressions in an endoribonuclease-dependent manner. However, the proteasome and autophagy systems did not influence protein levels of OAS1 and RNase L. These results suggest that Nsp11 does not directly regulate the protein levels of OAS1 and RNase L. Thus, we detected the mRNA levels of OAS1 and RNase L in Nsp11 overexpressed cells. The real-time PCR analysis showed that Nsp11 decreased the mRNA levels of OAS1 and RNase L in an endoribonuclease-dependent manner. Meanwhile, Baf A1 could rescue Nsp11-induced reduction of OAS1 and RNase L mRNA. It is likely that PRRSV Nsp11 inhibits activation of OAS/RNase L pathway by decreasing mRNA levels of OAS1 and RNase L. Our findings reveal that PRRSV Nsp11 decreases the protein level of OAS1 and RNase L to inhibit the activation of OAS/RNase L pathway and promote PRRSV replication, suggesting a potential mechanism for viral evasion of host innate immunity in an autophagy-dependent manner. Conclusion Taken together, the endoribonuclease activity of PRRSV Nsp11 antagonizes the activation of the OAS/RNase L pathway to promote PRRSV replication. Our results demonstrate a novel mechanism that Nsp11 inhibits the antiviral function of the OAS/RNase L pathway, which probably leads to persistent PRRSV infection.

Porcine deltacoronavirus (PDCoV) poses a growing threat to animal health and the pig industry. Given the scarcity of vaccines and antivirals targeting PDCoV, versatile and broadly adopted research techniques, such as reverse genetics (RG), are critical for understanding its biology and pathogenesis. In this study, we constructed a DNA-launched infectious cDNA clone of the highly pathogenic PDCoV (HP-PDCoV) strain GNU-2105 and explored the effect of the infectious dose on disease outcomes in neonatal piglets using the rescued icGNU-2105 virus. The icGNU-2105 virus displayed comparable in vitro virological characteristics as the parental virus. To assess the infectious dose-dependent pathogenicity of icGNU-2105, piglets were assigned to the high-dose group (HDG; 1 × 10 5 50% tissue culture infectious dose [TCID 50 ]/pig), medium-dose group (MDG; 1 × 10 4 TCID 50 /pig), or low-dose group (LDG; 1 × 10 3 TCID 50 /pig). Most clinical indicators of virulence were most severe in the HDG, including an increased neonatal mortality rate (75%), reduced average daily weight gain, and severe intestinal lesions. However, other virulence parameters, such as fecal viral shedding, intestinal viral loads, histopathological scores, and villus height-to-crypt depth ratios, were worse in the MDG and LDG than in the HDG. Further meta-analysis confirmed that clinical severity was significantly greater in the HDG, whereas excretion indicators tended to be more significant in the lower infectious dose group. Collectively, these findings provide new insights into the infectious dose-dependent pathogenicity of HP-PDCoV for establishing better control strategies. In addition, our HP-PDCoV–based RG platform provides a valuable tool for investigating virulence determinants and host–virus interactions and developing vaccines and antivirals.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a globally distributed and financially significant viral pathogen affecting the swine industry. Its extensive genotypic and pathotypic heterogeneity among strains makes disease control challenging. Since first reported in 2022, NADC34-like (lineage 1A, L1A) strains have become predominant in South Korea, attracting substantial attention in the domestic swine industry due to their high pathogenicity and considerable economic impact. This study aimed to explore age-dependent disease severity by comparing the pathogenicity of the Korean NADC34-like PRRSV strain GNU-2353 in 4-week-old (4WO) weaned and 10-week-old (10WO) growing pigs. The 4WO pigs exhibited most of the clinical indicators of virulence, including a high mortality rate (25%), hyperthermia, reduced average daily weight gain (ADWG), elevated viral loads in various tissues, thymic atrophy, and extensive interstitial pneumonia. Although the 10WO challenge group showed some criteria of virulent infection, such as high fever, low ADWG, and apparent lung lesions, other indicators (viremia, nasal shedding, viral load without mortality, and thymus atrophy) were less severe than those in the 4WO challenge group. Further meta-analysis confirmed that excretion indicators were significantly higher and clinical signs tended to be more severe in 4WO pigs. GNU-2353 infection induced faster and stronger antibody responses in 10WO pigs than in 4WO pigs, while inflammatory cytokine responses were more evident in 4WO pigs. These results showed that pig age influences the outcomes of GNU-2353 infection, mirroring antibody and cytokine responses. These findings provide insights into the age-dependent pathogenesis of NADC34-like viruses for the establishment of better control measures.

A novel classical swine fever virus (CSFV) strain GNU-240601 was identified from a commercial live Japanese encephalitis virus (JEV) vaccine. The whole-genome sequence of GNU-240601 shared the highest similarity with strains belonging to subgenotype 1.1. This is the first identification and complete genome sequence of CSFV from the JEV vaccine.

Importance: Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus that threatens the pig industry and acts as a viral spillover, infecting other farm animals and potentially humans. The recent emergence of highly pathogenic PDCoV in South Korea, causing severe neonatal piglet mortality, underscores the urgent need for effective countermeasures to mitigate economic and public health risks. Thus, discovering new therapeutic methods through drug repurposing is crucial for controlling PDCoV. Objective: This study investigated ivermectin (IVM) for its antiviral effect on PDCoV in vitro and explored its mechanism of action. Methods: The antiviral effects and mechanism of action of IVM against PDCoV were evaluated using various virological assays. Results: IVM markedly impaired the replication of PDCoV in a dose-dependent manner. Time-of-addition assays showed that the anti-PDCoV activity of IVM was most potent when administered before infection, simultaneously with infection, or immediately after infection. Further mode of action experiments revealed that IVM targeted the replication stage of PDCoV infection at post-entry steps. Conclusions and Relevance: Our results indicated that IVM interfered with PDCoV genome replication by impairing viral RNA synthesis. These findings suggest the potential of IVM for inhibiting PDCoV RNA polymerase and provide an invaluable therapeutic strategy to combat PDCoV infection with IVM, offering a viable alternative in the absence of commercial vaccines.

Localized heavy rainfall due to climate change has led to the frequent inundation of sewage treatment facilities, consequently causing significant secondary impacts such as water pollution and industrial paralysis. To address this, this study quantitatively reflected the specific characteristics and importance of environmental facilities to develop a more practical flood vulnerability assessment method. The proposed flood vulnerability index consists of a Hazard Index and a Mitigation Index. The former quantifies the risk level based on 1D/2D coupled inundation simulation results, and considers the importance of facilities and the location of key equipment. The latter evaluates structural and non-structural response capabilities through a checklist. A pilot application to the Gwangju Sewage Treatment Plant confirmed that the developed method can derive a quantitative vulnerability score reflecting both physical inundation threats and the facility’s mitigation capacity. This assessment technique is expected to serve as a practical tool for quantitatively diagnosing facility-specific vulnerabilities, thereby supporting preemptive disaster prevention planning and investment prioritization for critical environmental infrastructure.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a globally endemic, costly swine arterivirus with wide genetic and antigenic variations, leading to the frequent appearance of novel virulent strains that hampers PRRSV control. Recently, NADC30-like (lineage 1C, L1C) and NADC34-like (lineage 1A, L1A) PRRSV strains were reported to be prevalent in mainland South Korea and became the main epidemic strains persistently attributed to PRRSV outbreaks nationwide, raising great concern in the domestic pork industry. Although the genotypic and pathotypic variability of NADC30- and NADC34-like viruses has been explored in the United States and China, their genomic and biological characteristics have been scarcely studied in South Korea. Here, NADC34-like GNU-2353 and NADC30-like GNU-2377 strains were independently identified from vaccinated swine herds experiencing high piglet mortality. Whole-genome sequencing and phylogenetic analysis revealed that GNU-2353 and GNU-2377 clustered into sublineages L1A (NADC34-like) and L1C (NADC30-like), respectively, sharing high genomic homology with their corresponding lineage-representative strains and harboring the same molecular signatures of continuous 100 and discontinuous 131 amino acid deletions in the nsp2-coding region, respectively. Recombination detection indicated that GNU-2353 and GNU-2377 were recombinants and evolved through natural interlineage recombination between NADC34-like (L1A, major parent) or NADC30-like (L1C, major parent) and RespPRRS modified live virus (MLV)-like (lineage 5, minor parent) strains, respectively. Both viruses displayed homogenous growth kinetics but replicated faster than the prototype VR-2332 in a porcine alveolar macrophage cell line (PAM-KNU). The transcriptional profiles of immune response genes in infected PAM-KNU cells varied between the isolates and VR-2332; particularly, interleukin-10 expression was dramatically upregulated in cells infected with GNU-2353 and GNU-2377. Piglets with GNU-2353 and GNU-2377 infection had high fever; weight loss; increased viremia and nasal shedding; viral distribution in various tissues; thymic atrophy; and apparent macroscopic and microscopic lung lesions, including interstitial pneumonia and viral colonization, compared with control piglets, suggesting that both isolates were virulent to pigs. Remarkably, GNU-2353 caused higher fever, mortality rate (40%) with cyanosis, viremia, and viral shedding within 2 weeks and significantly higher viral loads in several organs than GNU-2377 infection. Thus, NADC34-like GNU-2353 was more pathogenic than NADC30-like GNU-2377. Our findings provide insights into the current epizootic circumstance of NADC30- and NADC34-like PRRSV in South Korea and can aid in tailoring improved control strategies.

IMPORTANCE:Porcine deltacoronavirus (PDCoV) is an emerging swine enteric coronavirus that threatens the pig industry and acts as a viral spillover, infecting other farm animals and potentially humans. The recent emergence of highly pathogenic PDCoV in South Korea, causing severe neonatal piglet mortality, underscores the urgent need for effective countermeasures to mitigate economic and public health risks. Thus, discovering new therapeutic methods through drug repurposing is crucial for controlling PDCoV. OBJECTIVE:This study investigated ivermectin (IVM) for its antiviral effect on PDCoV in vitro and explored its mechanism of action. METHODS:The antiviral effects and mechanism of action of IVM against PDCoV were evaluated using various virological assays. RESULTS:IVM markedly impaired the replication of PDCoV in a dose-dependent manner. Time-of-addition assays showed that the anti-PDCoV activity of IVM was most potent when administered before infection, simultaneously with infection, or immediately after infection. Further mode of action experiments revealed that IVM targeted the replication stage of PDCoV infection at post-entry steps. CONCLUSIONS AND RELEVANCE:Our results indicated that IVM interfered with PDCoV genome replication by impairing viral RNA synthesis. These findings suggest the potential of IVM for inhibiting PDCoV RNA polymerase and provide an invaluable therapeutic strategy to combat PDCoV infection with IVM, offering a viable alternative in the absence of commercial vaccines.

IMPORTANCE:Porcine circovirus (PCV) is a global concern due to its financial impact on the pig industry. Molecular epidemiology of PCV2 and PCV3 in wild boars is essential for understanding viral dispersal and evolution in the wild boar population. OBJECTIVE:This study aimed to assess the prevalence and genotypic traits of PCV2 and PCV3 in wild boars in the Gyeongnam region. METHODS:Serum samples from wild boars in Gyeongnam Province were screened for PCV2 and PCV3, and polymerase chain reaction-positive samples were further subjected to genotyping and whole-genome sequencing of PCV2 and PCV3. RESULTS:Thirty-eight samples tested positive for PCV2, 7 for PCV3, and 2 for PCV2 and PCV3 (coinfection). PCV2d and PCV3b are the dominant genotypes, causing PCV2 and PCV3 coinfections. Wild boar PCV2 and PCV3 viruses closely resemble their corresponding genotypic strains circulating in South Korea. CONCLUSIONS AND RELEVANCE:The circulation of PCV2 and/or PCV3 in wild species poses an additional challenge for commercial pig farming due to potential contact with infected wild boars. Our findings highlight the necessity for active monitoring and surveillance of wild boars and the enforcement of stringent biosecurity measures on commercial swine farms to mitigate the risk of PCV spillover to the domestic pig population.

Porcine deltacoronavirus (PDCoV) is an enteropathogenic swine coronavirus that causes severe diarrheal disease in suckling piglets and young pigs, leading to death. Transfer of maternal neutralizing antibodies from sows to piglets is critical to protecting piglets from PDCoV. Therefore, highly immunogenic antigens are required for the development of effective vaccine. Here, we produced plant-based recombinant protein vaccine against PDCoV in the form of bacteria-like particles (BLPs) using Lactococcus lactis to enhance the antigenicity. The S1 domain of spike protein from KNU16-07 strain was used as an antigen. The antigen was fused with lysine motifs ( Lys M) and coiled domains of coronin 1 (ccCor1) for L. lactis surface display. This fusion strategy facilitated the separation of the expressed proteins and increased antigenicity. The recombinant proteins were expressed in Nicotiana benthamiana and purified as BLPs. To determine whether PDCoV S1-coated BLPs could be immunized in the absence of adjuvants, plasma samples were obtained from mice injected with antigen. In conclusion, the PDCoV S1 domain generated from N. benthamiana excellently produced antibodies as a potential antigen and can be considered as an effective vaccine for passive immunization of piglets against PDCoV.

Porcine reproductive and respiratory syndrome (PRRS) is the most economically significant disease caused by porcine reproductive and respiratory syndrome virus (PRRSV). Type I interferon (IFN) induces a large number of interferon-stimulated genes (ISGs) expression to inhibit PRRSV infection. To survive in the host, PRRSV has evolved multiple strategies to antagonize host innate immune response. Previous studies have reported that PRRSV N protein decreases the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress IFN-β production. However, whether other PRRSV proteins inhibit the antiviral function of TRIM25 is less well understood. In this study, we first found that PRRSV NSP1α decreased ISGylation of TRIM25. Meanwhile, NSP1α significantly suppressed TRIM25-mediated IFN-β production to promote PRRSV replication. Further studies demonstrated that PRRSV NSP1α reduced the protein level of TRIM25 in proteasome system but did not regulate the transcription level of TRIM25. In addition, the function of NSP1α in TRIM25 degradation did not rely on its papain-like cysteine protease activity. Taken together, PRRSV NSP1α antagonizes the antiviral response of TRIM25 by mediating TRIM25 degradation to promote PRRSV replication. Our data identify TRIM25 as a natural target of PRRSV NSP1α and reveal a novel mechanism that PRRSV induces TRIM25 degradation and inhibits host antiviral immune response.

Coronaviruses (CoVs) belonging to the Gamma-CoV and Delta-CoV genera are widespread in poultry and wildfowl. Migratory birds, particularly duck species, serve as hosts for CoVs and play a pivotal role in transmitting the viruses to other species, including mammals. Despite the potential risks to animals and humans, there remains a narrow knowledge of the genetic and epidemiological properties of CoVs in wild birds. The current research aimed to detect and characterize CoVs present in migratory duck species (Anas acuta, Anas platyrhynchos, and Anas poecilorhyncha) from South Korea. Employing two rounds of pan-CoV real-time reverse transcription-polymerase chain reaction (RT-PCR) and nested PCR (nPCR) assays amplifying the conserved RNA-dependent RNA polymerase (RdRp) portion common to all known CoVs, we screened 2120 duck fecal samples collected during 2022-2023. The results indicated the presence of CoVs in 4.2% (91/2120) of samples from migratory ducks. Nucleotide sequencing of the RdRp gene revealed that all identified CoVs were clustered within the Gamma-CoV genus. Further phylogenetic analysis suggested that South Korean gamma-CoVs belong to the Igacovirus subgenus and share similarities with those found worldwide, highlighting the critical role of migratory ducks in introducing and exporting avian CoVs. We discovered two clade VII igacovirus strains in wild ducks closely related to those in pigeons, implying potential cross infection between these avian species. Overall, our study underscores the importance of active surveillance and monitoring of avian CoVs in wild birds as a preemptive response against the forthcoming emergence of new CoV species that can threaten both animal and human health.

Regdanvimab, a monoclonal antibody pharmaceutical, is the first Korean drug approved for treating coronavirus disease 2019 (COVID-19). We analyzed the therapeutic efficacy of regdanvimab in patients with the COVID-19 delta variant infection. We retrospectively reviewed the electronic medical records of patients hospitalized at two Korean tertiary COVID-19 hospitals with COVID-19 delta variant infection between May 26, 2021, and January 30, 2022. To analyze the therapeutic efficacy of regdanvimab, the patients were divided into regdanvimab and non-regdanvimab groups and were 1:1 propensity-score (PS)-matched on age, severity at admission, and COVID-19 vaccination history. Of 492 patients, 262 (53.3

Purpose: Accidental vaccination with a live attenuated low-virulence strain of Miyagi (LOM) vaccine led to the reemergence of classical swine fever virus (CSFV) in Jeju province, South Korea in 2014. To control the continual outbreaks of LOM-derived CSFV, the provincial government launched a provincial mass vaccination project using a CSF-E2 subunit vaccine. We conducted this study to assess the herd immunity level and outcomes of E2 vaccine-based immunization in breeding and growing herds on Jeju Island during 2020-2021. Materials and Methods: A large-scale vaccination trial using the Bayovac CSF-E2 vaccine investigated its efficacy in breeding and growing herds under farm application conditions (10 CSFV-affected and three CSFV-naive swine farms). Results: The level of herd immunity in each farm was classified into three (S1-S3) and six (G1-G6) profiles in breeding and growing herds, respectively. Immunity monitoring revealed a remarkable improvement in the herd immunity status in all farms. The majority (10/13) of farms, including CSFV-free farms, showed the S1G1 immunity profile in 2021, indicating the appropriate implementation of the advised vaccination regime. Moreover, there were significant decreases in Erns seropositivity from 100% to 50% and 25.9% to 4.3% at farm and pig levels, respectively. In particular, all farms were confirmed as CSFV free in the growing-finishing herds. Conclusion: Our large-scale trial demonstrated the effectiveness of the E2 subunit vaccine in establishing herd immunity stabilization and eliminating CSFV circulation in the affected farms and highlighted the need for a provincial vaccination policy to regain the CSF-free status on Jeju Island.

ABSTRACT Porcine Mx1 is a type of interferon-induced GTPase that inhibits the replication of certain RNA viruses. However, the antiviral effects and the underlying mechanism of porcine Mx1 for porcine reproductive and respiratory syndrome virus (PRRSV) remain unknown. In this study, we demonstrated that porcine Mx1 could significantly inhibit PRRSV replication in MARC-145 cells. By Mx1 segment analysis, it was indicated that the GTPase domain (68-341aa) was the functional area to inhibit PRRSV replication and that Mx1 interacted with the PRRSV-N protein through the GTPase domain (68-341aa) in the cytoplasm. Amino acid residues K295 and K299 in the G domain of Mx1 were the key sites for Mx1-N interaction while mutant proteins Mx1(K295A) and Mx1(K299A) still partially inhibited PRRSV replication. Furthermore, we found that the GTPase activity of Mx1 was dominant for Mx1 to inhibit PRRSV replication but was not essential for Mx1-N interaction. Finally, mechanistic studies demonstrated that the GTPase activity of Mx1 played a dominant role in inhibiting the N-Nsp9 interaction and that the interaction between Mx1 and N partially inhibited the N-Nsp9 interaction. We propose that the complete anti-PRRSV mechanism of porcine Mx1 contains a two-step process: Mx1 binds to the PRRSV-N protein and subsequently disrupts the N-Nsp9 interaction by a process requiring the GTPase activity of Mx1. Taken together, the results of our experiments describe for the first time a novel mechanism by which porcine Mx1 evolves to inhibit PRRSV replication. IMPORTANCE Mx1 protein is a key mediator of the interferon-induced antiviral response against a wide range of viruses. How porcine Mx1 affects the replication of porcine reproductive and respiratory syndrome virus (PRRSV) and its biological function has not been studied. Here, we show that Mx1 protein inhibits PRRSV replication by interfering with N-Nsp9 interaction. Furthermore, the GTPase activity of porcine Mx1 plays a dominant role and the Mx1-N interaction plays an assistant role in this interference process. This study uncovers a novel mechanism evolved by porcine Mx1 to exert anti-PRRSV activities.

Non-POU domain-containing octamer-binding protein (NONO) is a multi-functional nuclear protein which belongs to the Drosophila behavior/human splicing (DBHS) protein family. NONO is known to regulate multiple important biological processes including host antiviral immune response. However, whether NONO can inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication is less well understood. In this study, we demonstrated that swine NONO (sNONO) inhibited PRRSV replication, via increasing expression of IFN-β, whereas NONO knockdown or knockout in PAM-KNU cells was more susceptible to PRRSV infection. As an IRF3 positive regulation factor, NONO promoted IFN-β expression by enhancing activation of IRF3. During PRRSV infection, NONO further up-regulated IRF3-mediated IFN-β expression by interacting with PRRSV N protein. Mechanistically, NONO functioned as a scaffold protein to detect PRRSV N protein and formed N-NONO-IRF3 complex in the nucleus. Interestingly, it was found that the NONO protein reversed the inhibitory effect of PRRSV N protein on type I IFN signaling pathway. Taken together, our study provides a novel mechanism for NONO to increase the IRF3-mediated IFN-β activation by interacting with the viral N protein to inhibit PRRSV infection.

Foot-and-mouth disease virus (FMDV) has developed various strategies to antagonize the host innate immunity. FMDV Lpro and 3Cpro interfere with type I IFNs through different mechanisms. The structural protein VP3 of FMDV degrades Janus kinase 1 to suppress IFN-γ signaling transduction. Whether non-structural proteins of FMDV are involved in restraining type II IFN signaling pathways is unknown. In this study, it was shown that FMDV replication was resistant to IFN-γ treatment after the infection was established and FMDV inhibited type II IFN induced expression of IFN-γ-stimulated genes (ISGs). We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-γ-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. 3Cpro expression significantly reduced the ISGs transcript levels and palindromic gamma-activated sequences (GAS) promoter activity, without affecting the protein level, tyrosine phosphorylation, and homodimerization of STAT1. Finally, we provided evidence that 3C protease activity played an essential role in degrading KPNA1 and thus inhibited ISGs mRNA and GAS promoter activities. Our results reveal a novel mechanism by which an FMDV non-structural protein antagonizes host type II IFN signaling.