It is shown that GSDMA deficiency increases viral loads but reduces inflammation, tissue damage, and mortality upon infection, suggesting that disease severity is driven more by inflammation than by viral load.
Abstract
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.
This study demonstrates that porcine GSDMD-CT inhibits IFN-I signaling and promotes porcine epidemic diarrhea virus (PEDV) replication and finds that the PEDV-encoded PLP2 protein directly interacts with GSDMD-CT, resulting in mutual stabilization.
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Klebsiella pneumoniae is a major cause of multidrug-resistant and hypervirulent infections worldwide, highlighting the urgent need for host-directed therapeutic strategies that complement conventional antibiotics. Emerging evidence suggests that K. pneumoniae promotes intracellular persistence by suppressing host SUMOy...
Gal3 is identified as a potent host factor that orchestrates excessive inflammation by simultaneously facilitating viral entry and driving the assembly of the NLRP3 inflammasome, highlighting the Gal3-NLRP3 axis as a promising therapeutic target to mitigate severe influenza-induced lung injury.
Zih-Syuan Yang, A. Thitithanyanont, Jason C. Huang et al.· International Journal of Bio...· 0 citations
Background Macrophage-mediated inflammation critically determines malaria pathology. Although pyroptosis contributes to host defense, excessive activation induces severe immunopathology. The precise pyroptotic pathways in splenic macrophages during Plasmodium infection, and the upstream regulatory mechanisms that gover...
Yu-Mei Gong, Yi-Wei Liu, Long-Kun Li et al.· Frontiers in Immunology· 0 citations
Middle East respiratory syndrome coronavirus (MERS-CoV) is a merbecovirus associated with recurrent zoonotic spillover and severe lower-respiratory disease. Research has focused largely on DPP4-mediated entry, spike structure, replicase biology, neutralizing antibodies, and vaccines. However, the 3′-encoded accessory p...
Chun-Hua Wang, Xu-Hang Li, Yi Jiang et al.· Frontiers in Immunology· 0 citations
It is demonstrated that nanobodies targeting the PLpro/ISG15 interface can achieve synergistic antiviral and immunomodulatory effects, providing a proof-of-concept for a novel therapeutic approach to combat SARS-CoV-2 and potentially other emerging coronaviruses.
Guo-Long Liu, Jian-Tao Chen, Fang Wu et al.· Journal of Virology· 0 citations
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