Differential replication, pathology, and immune response of clade IIb mpox virus in C57BL/6 and BALB/c mice

We have previously established a clade IIb mpox virus (MPXV) pathogenic BALB/c mouse model for developing mpox countermeasures. Here, we comprehensively investigated the susceptibility of BALB/c and C57BL/6 mice to MPXV and found that Clade IIb MPXV was capable of rapid replication in the lungs of both mouse strains, thus triggering similar dynamic pathological changes and antibody responses. However, C57BL/6 mice, compared to BALB/c mice, seem less susceptible to MPXV, evidenced by no significant weight loss, lower viral load, faster viral clearance, and earlier pathological improvement, as well as weaker antibody response. Interestingly, C57BL/6 <i>stat1</i>^-/- mice intranasally infected with MPXV displayed a significant body weight loss, indicating the crucial role of innate immunity in the susceptibility to MPXV. The C57BL/6 model mimics clinical characteristics of asymptomatic or mildly symptomatic patients with mild mpox, which will be beneficial for exploring MPXV infection, transmission, pathogenesis, and immune responses.