Although Gasdermin A (GSDMA) drives inflammation by inducing pyroptosis, its specific role in antiviral defense remains unclear. Here we identify GSDMA as an immunomodulatory protein activated in response to coronavirus (CoV) infection. Specifically, CoV-encoded protease nsp5 cleaves GSDMA at two conserved glutamine sites, Q247 and Q187. Cleavage at Q247 liberates an active N-terminal fragment (GSDMA_1-247) that triggers pyroptosis, promotes inflammation, and restricts viral replication. In contrast, cleavage at the alternative site Q187 attenuates this function. Using Gsdma-/- mice, we show that GSDMA deficiency increases viral loads but reduces inflammation, tissue damage, and mortality upon infection. These findings suggest that disease severity is driven more by inflammation than by viral load. Our findings reveal a novel mechanism of antiviral immunity and inflammatory regulation via CoV nsp5-mediated dual cleavage of GSDMA, highlighting a potential target for combined antiviral and anti-inflammatory therapies.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant pathogen in swine, causing substantial economic losses globally. The host acute-phase response to PRRSV infection and its role in antiviral defense remain poorly understood. In this study, we identify serum amyloid A2 (SAA2) as a key acute-phase protein that is induced during PRRSV infection and demonstrate its potent antiviral activity against this virus. While both SAA2 and SAA3 were upregulated in PRRSV-infected primary porcine alveolar macrophages, functional analyses revealed that SAA2 exerted anti-PRRSV effects. Both the ectopic expression of SAA2 and treatment with recombinant SAA2 protein significantly inhibited PRRSV replication in cultured cells. Mechanistically, SAA2 directly binds to PRRSV particles through interactions with phosphatidylinositol 4,5-bisphosphate (PIP2), a host-derived lipid membrane component in the virus particles, as well as the major envelope glycoprotein GP5. The anti-PRRSV activity of SAA2 was counteracted by high-density lipoprotein (HDL), revealing a physiological regulatory mechanism. Structure-function analysis further identified the N-terminal α-helix (encoded by exon 1) as essential for SAA2-mediated viral inhibition. Our findings unveil a novel antiviral strategy in which a host acute-phase protein directly targets enveloped virions, highlighting SAA2 as a potential target for intervention against PRRSV.
Shuai Li, Yuanxiang Xiong, L. Fang et al.· Antiviral Research· 0 citations
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