Seneca Valley Virus (SVV), a member of the Picornaviridae family, is an emerging porcine virus that can cause vesicular disease in pigs. However, the immune evasion mechanism of SVV remains unclear, as does its interaction with other pathways. STING (Stimulator of interferon genes) is typically recognized as a critical factor in innate immune responses to DNA virus infection, but its role during SVV infection remains poorly understood. In the present study, we observed that STING was degraded in SVV-infected PK-15 cells, and SVV replication in the cells was affected when STING was knockdown or overexpressed. The STING degradation observed was blocked when the SVV-induced autophagy was inhibited by using autophagy inhibitors (Chloroquine, Bafilomycin A1) or knockdown of autophagy related gene 5 (ATG5), suggesting that SVV-induced autophagy is responsible for STING degradation. Furthermore, the STING degradation was inhibited when reticulophagy regulator 1 (FAM134B), a reticulophagy related receptor, was knocked down, indicating that SVV infection induces STING degradation via reticulophagy. Further study showed that in eukaryotic translation initiation factor 2 alpha kinase 3 (PERK)/activating transcription factor 6 (ATF6) deficient cells, SVV infection failed to induce reticulophagy-medaited STING degradation, indicating that SVV infection caused STING degradation via PERK/ATF6-mediated reticulophagy. Notably, blocking reticulophagy effectively hindered SVV replication. Overall, our study suggested that SVV infection resulted in STING degradation via PERK and ATF6-mediated reticulophagy, which may be an immune escape strategy of SVV. This finding improves the understanding of the intricate interplay between viruses and their hosts and provides a novel strategy for the development of novel antiviral drugs.

Foot-and-mouth disease (FMD) is an acute contagious disease of cloven-hoofed animals such as cattle, pigs, and sheep. Current emergency FMD vaccines are of limited use for early protection because their protective effect starts 7 days after vaccination. Therefore, antiviral drugs or additives are used to rapidly stop the spread of the virus during FMD outbreaks. Manganese (Mn²⁺) was recently found to be an important substance necessary for the host to protect against DNA viruses. However, its antiviral effect against RNA viruses remains unknown. In this study, we found that Mn²⁺ has antiviral effects on the FMD virus (FMDV) both in PK15 cells and mice. The inhibitory effect of Mn²⁺ on FMDV involves NF-κB activation and up-regulation of interferon-stimulated genes. Animal experiments showed that Mn²⁺ can be highly effective in protecting C57BL/6N mice from being infected with FMDV. Overall, we suggest Mn²⁺ as an effective antiviral additive for controlling FMDV infection.

Foot-and-mouth disease (FMD) is one of the most contagious livestock diseases in the world, posing a constant global threat to the animal trade and national economies. The chemokine C-X-C motif chemokine ligand 13 (CXCL13), a biomarker for predicting disease progression in some diseases, was recently found to be increased in sera from mice infected with FMD virus (FMDV) and to be associated with the progression and severity of the disease. However, it has not yet been determined which cells are involved in producing CXCL13 and the signaling pathways controlling CXCL13 expression in these cells. In this study, the expression of CXCL13 was found in macrophages and T cells from mice infected with FMDV, and CXCL13 was produced in bone-marrow-derived macrophages (BMDMs) by activating the nuclear factor-kappaB (NF-κB) and JAK/STAT pathways following FMDV infection. Interestingly, CXCL13 concentration was decreased in sera from interleukin-10 knock out (IL-10^-/-) mice or mice blocked IL-10/IL-10R signaling in vivo after FMDV infection. Furthermore, CXCL13 was also decreased in IL-10^-/- BMDMs and BMDMs treated with anti-IL-10R antibody following FMDV infection in vitro. Lastly, it was demonstrated that IL-10 regulated CXCL13 expression via JAK/STAT rather than the NF-κB pathway. In conclusion, the study demonstrated for the first time that macrophages and T cells were the cellular sources of CXCL13 in mice infected with FMDV; CXCL13 was produced in BMDMs via NF-κB and JAK/STAT pathways; and IL-10 promoted CXCL13 expression in BMDMs via the JAK/STAT pathway.

Introduction: Foot-and-mouth disease (FMD) is a highly contagious infectious disease caused by foot-and-mouth disease virus (FMDV). FMDV replicates not only in epithelial cells, where it induces vesicular lesions, but also in myocardial and skeletal muscle tissues, leading to myocarditis and even fatal outcomes in infected animals. RIPK3/MLKL-mediated necroptosis is a proinflammatory cell death process that plays a significant role in viral infections. However, whether FMDV infection can trigger necroptosis in host cells remains unclear. Methods: We assessed necroptosis induced by FMDV infection through activation of the RIPK3/MLKL pathway in PK-15 and BHK-21 cells. Specific inhibitors GSK’872 (targeting RIPK3 phosphorylation) and NSA (targeting MLKL phosphorylation) were applied to examine the impact of this pathway on viral replication. Additionally, Co-immunoprecipitation (Co-IP) was used to analyze the interactions between FMDV-encoded proteins and RIPK3/MLKL, and AlphaFold3 was used to predict the interaction interface between the 3D protein and the RHIM-containing region of RIPK3. Results: FMDV infection activated the RIPK3/MLKL pathway and induced necroptosis in both PK-15 and BHK-21 cells. Inhibitor assays revealed that blocking RIPK3 or MLKL phosphorylation significantly reduced FMDV VP1 expression and viral titers, indicating that the necroptosis pathway favors FMDV replication. Further investigation revealed that the FMDV non-structural protein 3D is the key protein responsible for activating RIPK3/MLKL pathway. Moreover, we confirmed that the 3D protein interacts and colocalizes with RIPK3. AlphaFold3 structural prediction suggested that 3D can directly associate with the RHIM-containing region of RIPK3, with residues R320, H322, E324, and Y346 of 3D interacting with residues N466, V469, and K471 of RIPK3 at the interface. Discussion: Our results demonstrate that FMDV infection induces necroptosis in host cells. This finding expands the modes of host cell death caused by FMDV infection, advances the understanding of the role of necroptosis in viral infections, and may help elucidate the pathogenic mechanisms of FMDV.