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

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

  • Cell Rep Med. 2025 May 20;6(5):102135. doi: 10.1016/j.xcrm.2025.102135.
Lin Zhu 1,  Qi Liu 1,  Yongzhi Hou 1,  Baoying Huang 2,  Dong Zhang 1,  Zhe Cong 1,  Jianrong Ma 1,  Na Li 1,  Jiahan Lu 1,  Jingjing Zhang 1,  Lingyan Zhang 1,  Ting Chen 1,  Qiang Wei 3,  Jiangning Liu 1,  Wenjie Tan 4,  Jing Xue 5
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 2 NHC Key Laboratory of Biosafety, National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
  • 3 NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China.
  • 4 NHC Key Laboratory of Biosafety, National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China. Electronic address: tanwj@ivdc.chinacdc.cn.
  • 5 NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China. Electronic address: xuejing@cnilas.org.
PMID: 40398389 DOI: 10.1016/j.xcrm.2025.102135
Abstract

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.

Keywords

CAST/EiJ mice; IFN-α/β; STING; monkeypox virus; rhesus macaques; splenomegaly.

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