Since 2022, the monkeypox virus (MPXV) has ceased to be a regionally endemic zoonotic disease limited to Africa and has become a global concern. Over 129,000 cases have been recorded worldwide. Researchers seek reliable models to study pathogenesis, develop vaccines, and test treatments for monkeypox. One such model is the CAST/EiJ mouse, which is highly susceptible to MPXV due to a low number of NK cells. Unlike primates, these mice respond to MPXV infection but do not develop skin lesions or rashes.
MPXV is an enveloped double-stranded DNA virus. Host cells detect the viral DNA through cGAS receptors. Upon sensing viral DNA, cGAS synthesizes the signaling molecule cGAMP, which binds to the STING protein, initiating a cascade that leads to type I interferon (IFN-I) production, including IFN-α and IFN-β.
Researchers from the Chinese Academy of Medical Sciences investigated:
- The ability of epidemic MPXV clade IIb to activate the cGAS-STING pathway in macrophages derived from CAST/EiJ mice
- The protective role of IFN-I against MPXV in CAST/EiJ mice and rhesus macaques
Compared to clade I MPXV strains, clade IIb has a lower mortality rate—up to 10% versus 1%. In the mouse model, MPXV infection did not cause weight loss or death. However, intraperitoneal infection led to lymphadenopathy and splenomegaly, associated with a significant increase in macrophages, T and B cells, NK cells, and dendritic cells. Additionally, there was a marked reduction in the CD4/CD8 ratio among splenic T cells—a key contributor to splenomegaly.
MPXV was detected in mouse lungs, though no signs of inflammation or central pathology were observed, suggesting either low replication or lack of sustained inflammation in lung tissue.
Clade IIb MPXV Activates cGAS-STING Pathway in Macrophages
While some poxviruses can block host sensitivity to viral DNA, MPXV activates the cGAS-STING signaling cascade. MPXV may enhance this pathway through its viral protein A29, which colocalizes with phosphorylated STING and TBK1 proteins. MPXV infection raises cell cGAMP levels, suggesting a dual mechanism of innate immune activation via DNA sensing and direct protein interaction.
IFN-β Suppresses MPXV Replication in Macrophages and Mice
IFN-β significantly reduced MPXV replication and alleviated splenomegaly in infected mice. Early administration of IFN-β maximized its antiviral effect by limiting viral spread. The best results were obtained when IFN-β was administered three hours before infection. Post-infection administration still offered protection, albeit less effectively.
IFN-α2b Reduces MPXV Severity in Rhesus Macaques
Rhesus macaques received either pegylated IFN-α2b or saline. In the IFN-α2b group, no significant changes in body temperature were observed, whereas the control group experienced moderate fever on day 7 post-infection. Body weight remained stable throughout the observation period in the IFN-α2b group.
Macaques treated with pegylated IFN-α2b developed fewer skin lesions, and plasma viral load was approximately 100 times lower than controls.
Although only one macaque completely cleared skin lesions, IFN-I is key in managing monkeypox in primates. The short half-life of IFN-β necessitates frequent dosing, whereas IFN-α2b is effective with less frequent administration. These results raise the possibility of combining IFN-I with other antiviral agents to treat monkeypox and optimize dosage, strategy, and delivery timing.
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