Pathogenic signatures and therapeutic evaluation of emergent MPXV Clade Ib in low-susceptibility and immunocompromised mouse models

Monkeypox (Mpox) is a zoonotic disease that threatens global public health. Different clades of monkeypox virus (MPXV) vary in transmissibility and pathogenicity. In 2023, a Clade Ib MPXV variant emerged in the Democratic Republic of the Congo, continued to spread in parts of Africa, and subsequently spilled over to other regions, posing new challenges for outbreak prevention and control. We established stable mouse models of MPXV Clade Ib infection by intranasally infecting C57BL/6/STAT1−/−, AGB6 (C57BL/6-Ifngr1−/−Ifnar1−/−), C57BL/6, and BALB/c mice. Susceptible strains showed marked body weight loss, high viral loads in tissues, and severe histopathological lesions. RNA-seq analysis of spleens at the early stage of infection showed that differentially expressed genes were mainly enriched in interferon-mediated antiviral pathways and inflammatory cytokine-related pathways, whereas genes associated with adaptive immune responses were downregulated. Comparative analysis showed that MPXV Clade Ib caused more severe disease phenotypes than Clade IIb under the same experimental conditions, which is consistent with reported differences in clinical severity. We established reproducible mouse models for MPXV Clade Ib infection and demonstrated that Clade Ib showed greater replication capacity and pathogenicity than Clade IIb in these models. This study also provides a foundation for subsequent research on the pathogenesis of MPXV and the evaluation of antiviral efficacy. Established diverse MPXV Clade Ib mouse models. Transcriptomics reveals immune-mediated pathogenic signatures. Clade Ib shows faster infection kinetics than Clade IIb in mice. Validated models for antiviral drug evaluation.