MPXV infection activates cGAS-STING signaling and IFN-I treatment reduces pathogenicity of mpox in CAST/EiJ mice and rhesus macaques.

The recent mpox outbreak underscores the urgent need for more accessible vaccines and treatments. However, the mpox virus (MPXV) clade IIb exhibits milder virulence and fails to develop typical pathological characteristics in mouse models. Herein, we found that CAST/EiJ mice infected intraperitoneally with MPXV clade IIb exhibited more efficient viral replication and experienced splenomegaly. Additionally, MPXV infection triggers the phosphorylation of stimulator of interferon genes (STING), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3) in ex vivo bone marrow-derived macrophages from mice and promotes the transcription of interferon (IFN)-β via the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway. Notably, IFN-β treatment significantly reduced viral replication and alleviated splenomegaly in MPXV-infected CAST/EiJ mice. In rhesus macaques, the clinically approved pegylated IFN alpha-2b treatment markedly reduced the severity of MPXV infection by alleviating skin lesions and lowering plasma viremia. These findings demonstrate that MPXV clade IIb activates the cGAS-STING pathway and highlight the potential of type I interferon (IFN-I) treatment in CAST/EiJ mice and rhesus macaques for mpox.