STING agonist diABZI confers protection against swine acute diarrhea syndrome coronavirus in neonatal mice by activating antiviral immunity

ABSTRACT The recently identified alphacoronavirus swine acute diarrhea syndrome coronavirus (SADS-CoV) has a high fatality rate in neonatal piglets. Currently, no vaccines or treatment strategies for SADS-CoV infection are available. The stimulator of interferon genes (STING) pathway plays a critical role in initiating innate immune responses against RNA viral infections; however, its role in host defense against SADS-CoV infection remains unexplored. We assessed the pathogenicity of SADS-CoV in 3-day-old, 7-day-old, and 3-week-old mice, revealing striking age-dependent susceptibility—a pattern mirroring clinical observations in piglets. Additionally, SADS-CoV infection activated the STING-dependent pathway, which resulted in significant interferon responses in infected mice. In vitro experimental findings confirmed that STING pathway activation inhibited SADS-CoV replication by modulating the NF-κB and IRF3 signaling pathways and mediating the production of inflammatory cytokines, which underscores the importance of the STING pathway in antiviral defense mechanisms. In vivo studies revealed that the STING inhibitor C176 significantly promoted viral replication, whereas activation of the STING pathway using the STING agonist diABZI increased antiviral immune responses and reduced viral replication. Notably, diABZI protected mice from SADS-CoV infection by reducing viral replication through mechanisms involving both type I interferon-dependent and -independent pathways. These results represent the first demonstration of the in vivo therapeutic efficacy of pharmacological STING activation against SADS-CoV. These findings demonstrate that the STING pathway serves as a critical regulator of host defense against SADS-CoV and suggest that STING-targeted intervention has therapeutic potential. IMPORTANCE Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging zoonotic pathogen with significant implications for veterinary and public health; it has a high mortality rate in piglets and the potential for cross-species transmission. Currently, there are no approved vaccines or specific antiviral agents available for this pathogen. In this study, we demonstrated that the stimulator of interferon genes (STING) pathway serves as a critical mediator of host defense against SADS-CoV infection. STING activation inhibits viral replication by coordinating interferon responses and modulating NF-κB/IRF3 signaling, and its inhibition exacerbates infection. Importantly, pharmacological activation of the STING pathway using the agonist diABZI significantly inhibited viral replication in vivo in a STING-dependent manner, with contributions from both type I interferon-dependent and -independent antiviral mechanisms, highlighting its therapeutic potential. These results advance our understanding of antiviral defense strategies against SADS-CoV and identify STING pathway regulation as a viable therapeutic approach for this emerging pathogen.