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Vesicular disease caused by Seneca Valley virus infection occurred in pigs from 5 outdoor pig farms in England during June-September 2022. Clinical signs resembled notifiable vesicular diseases, such as foot-and-mouth disease. Full genome sequences shared a common ancestor with a virus circulating in the United States.

Seneca Valley virus (SVV) infection leads to severe vesicular diseases in pigs, posing a significant threat to the global swine industry. Ferroptosis, a novel form of non-apoptotic cell death, is characterized by iron-dependent phospholipid peroxidation. However, the role of ferroptosis in SVV replication remains poorly understood. In this study, we demonstrate that SVV infection induces ferroptosis, as evidenced by lipid peroxidation, reactive oxygen species (ROS) accumulation, and glutathione (GSH) depletion. The GPX4 and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy are key contributors to ferroptosis induction. Furthermore, our findings reveal that the SVV 3 C proteinase (3C pro ) targets the GPX4 for degradation, thereby promoting ferroptosis. Simultaneously, the SVV 3D protein enhances the NCOA4-FTH1 interaction, leading to increased ferritin degradation and subsequent ferritinophagy. Notably, inhibition of ferroptosis significantly reduces SVV replication and its associated inflammatory effects. Collectively, these results elucidate the intricate molecular mechanisms underlying SVV-induced ferroptosis, highlighting the synergistic roles of 3C pro and 3D in activating ferroptotic pathways and presenting potential targets for therapeutic intervention in SVV infections.

Recently, the use of oncolytic viruses in cancer therapy has become a realistic therapeutic option. Seneca Valley Virus (SVV) is a newly discovered picornavirus, which has earned a significant reputation as a potent oncolytic agent. Anthrax toxin receptor 1 (ANTXR1), one of the cellular receptors for the protective antigen secreted by Bacillus anthracis, has been identified as the high-affinity cellular receptor for SVV. Here, we report the structure of the SVV-ANTXR1 complex determined by single-particle cryo-electron microscopy analysis at near-atomic resolution. This is an example of a shared receptor structure between a mammalian virus and a bacterial toxin. Our structure shows that ANTXR1 decorates the outer surface of the SVV capsid and interacts with the surface-exposed BC loop and loop II of VP1, “the puff” of VP2 and “the knob” of VP3. Comparison of the receptor-bound capsid structure with the native capsid structure reveals that receptor binding induces minor conformational changes in SVV capsid structure, suggesting the role of ANTXR1 as an attachment receptor. Furthermore, our results demonstrate that the capsid footprint on the receptor is not conserved in anthrax toxin receptor 2 (ANTXR2), thereby providing a molecular mechanism for explaining the exquisite selectivity of SVV for ANTXR1.

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and three-fold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.

Senecavirus A (SVA) is a positive-sense single-stranded RNA virus that belongs to the Senecavirus genus within the Picornaviridae family. The virus has been silently circulating in pig herds of the USA since 1988. However, cases of senecavirus-associated vesicular disease were reported in Canada in 2007 and in the USA in 2012. Since late 2014 and early 2015, an increasing number of senecavirus outbreaks have been reported in pigs in different producing categories, with this virus being detected in Brazil, China, and Thailand. Considering the novel available data on senecavirus infection and disease, 2015 may be a divisor in the epidemiology of the virus. Among the aspects that reinforce this hypothesis are the geographical distribution of the virus, the affected pig-producing categories, clinical signs associated with the infection, and disease severity. This review presents the current knowledge regarding the senecavirus infection and disease, especially in the last two years. Senecavirus epidemiology, pathogenic potential, host immunological response, diagnosis, and prophylaxis and control measures are addressed. Perspectives are focused on the need for complete evolutionary, epidemiological and pathogenic data and the capability for an immediate diagnosis of senecavirus infection. The health risks inherent in the swine industry cannot be neglected.

Seneca Valley virus (SVV) infection in pigs is associated with porcine idiopathic vesicular disease (PIVD). Outbreaks of SVV infection in pig herds have been reported in several Asia and Americas countries. Recently, a series of outbreaks of SVV infection occurred in China, Canada, Thailand and the United States. However, no available vaccines have been developed to limit the transmission of SVV. The SVV CH-FJ-2017 from Fujian province in China is a representative of the epidemic strains, and shows 98.5–99.9% capsid protein amino acid identity with the recent SVV strains. In the present study, we developed a SVV CH-FJ-2017 inactivated vaccine. The SVV was produced by cultivation of BHK-21 cells in roller bottles, inactivated with binary ethylenimine, and mixed with oil adjuvant (Montanide ISA). The immunogenicity of the inactivated vaccine in pigs was evaluated by neutralizing test, and the immunized pigs were challenged with SVV CH-FJ-2017. The results showed that animals receiving one dose of the inactivated vaccine (2 μg/dose) with oil adjuvant developed high neutralizing antibody titers and showed no clinical signs after virus challenge comparing with the non-vaccinated animals, indicating a good protective efficacy of the produced vaccine against SVV infection. This is the first reported SVV vaccine that can be used for control of SVV infection in pigs.

Seneca Valley virus (SVV), a new member of Picornaviridae , causes idiopathic vesicular symptoms in pregnant sows and acute death in neonatal piglets, considerably damaging the swine industry. The viral protease 3C (3C pro ) cleaves host immune-related molecules to create a favorable environment for viral replication. In this study, we found that mRNA decapping enzyme 1A (DCP1A) is a novel antiviral effector against SVV infection that targets 3D viral RNA-dependent RNA polymerase for OPTN-mediated autophagic degradation. To counteract this effect, SVV 3C pro targets DCP1A for cleavage at glutamine 343 (Q343), resulting in the cleaved products DCP1A (1–343) and DCP1A (344–580), which lose the ability to restrict SVV replication. In contrast, the 3C cleavage-resistant DCP1A-Q343A mutant exhibited stronger antiviral effects than the wild-type DCP1A. Additionally, the degradation of the viral 3D protein targeted by DCP1A was abolished after its cleavage by SVV 3C pro . In conclusion, our study demonstrated that SVV 3C pro is a pivotal ISG antagonist that cleaves DCP1A. These results offer novel insight into how viruses evade host immunity.

(SVA) is an emerging picornavirus causing vesicular disease (VD) clinically indistinguishable from foot-and-mouth disease (FMD) in pigs. Currently there are no vaccines currently available for SVA. Here we developed a recombinant SVA strain (rSVAm SacII) using reverse genetics and assessed its immunogenicity and protective efficacy in pigs. characterization of the rSVAm SacII strain demonstrated that the virus is attenuated, as evidenced by absence of lesions, decreased viremia and virus shedding in inoculated animals. Notably, while attenuated, rSVA mSacII virus retained its immunogenicity as high neutralizing antibody (NA) responses were detected in inoculated animals. To assess the immunogenicity and protective efficacy of rSVA mSacII, 4-week-old piglets were sham-immunized or immunized with inactivated or live rSVA mSacII virus-based formulations. A single immunization with live rSVA mSacII virus via the intramuscular (IM) and intranasal (IN) routes resulted in robust NA responses with antibodies being detected between days 3-7 pi. Neutralizing antibody responses in animals immunized with the inactivated virus via the IM route were delayed and only detected after a booster on day 21 pi. Immunization with live virus resulted in recall T cell proliferation (CD4 , CD8 , and CD4 /CD8 T cells), demonstrating efficient stimulation of cellular immunity. Notably, a single dose of the live attenuated vaccine candidate resulted in protection against heterologous SVA challenge, as demonstrated by absence of overt disease and reduced viremia, virus shedding and viral load in tissues. The live attenuated vaccine candidate developed here represents a promising alternative to prevent and control SVA in swine.

Gasdermin A (GSDMA) remains a protein shrouded in mystery, particularly regarding its regulation by virus-encoded proteases. Previous studies have identified human GSDMA (hGSDMA) as a sensor and substrate of the SpeB from group A Streptococcus , which initiates pyroptosis. However, it is not clear if viral proteases also cleave GSDMA. In this study, we show that a fragment of porcine GSDMA (pGSDMA) containing the first 252 residues constitutes the pore-forming domain responsible for inducing lytic cell death and pyroptosis. Interestingly, picornavirus Seneca Valley Virus (SVV) protease 3C cleaves both pGSDMA and hGSDMA, generating a shorter fragment that fails to associate with the plasma membrane and does not induce pyroptosis. This cleavage by SVV 3C suppresses GSDMA-mediated lactate dehydrogenase release, bactericidal activity, and lytic cell death. This study reveals how SVV subverts host inflammatory defense by disrupting GSDMA-induced pyroptosis, thereby advancing our understanding of antiviral immunity and opening avenues for treating GSDMA-associated autoimmune diseases.

Cyclic GMP-AMP synthetase (cGAS) is robustly expressed in the nucleus and tightly tethered by chromatin to prevent its activation with self-DNA. During stimulation or infection, nuclear cGAS is activated and translocates from the nucleus to the cytoplasm. However, the viral strategies specifically targeting nuclear cGAS are completely unexplored. Here, we discovered that protease 3C of Seneca Valley virus translocates from the cytoplasm to the nucleus upon viral infection, binds to nuclear DNA, and specifically cleaves H2A. Furthermore, DNA binding to 3C enhances the cleavage of nuclear cGAS within its N-terminal domain. The hindrance of cGAS translocation from the nucleus to the cytoplasm results in the suppression of IFN-I induction and leads to immune evasion. This work uncovers a unique mechanism wherein a viral protease binds to nuclear DNA and cleaves nuclear cGAS and histone H2A, leading to viral evasion of cGAS-mediated immune restriction.