Infection with mpox virus via the genital mucosae increases shedding and transmission in the multimammate rat (Mastomys natalensis)

The 2022 mpox virus outbreak was sustained by human-to-human transmission, however it is currently unclear which factors lead to sustained transmission of mpox virus (MPXV). Here, we present Mastomys natalensis as a model for MPXV transmission after intraperitoneal, rectal, vaginal, aerosol, and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Virus shedding and tissue replication was route-dependent and occurred in the presence of self-resolving localized skin, lung, reproductive tract, or rectal lesions. Mucosal inoculation via rectal, vaginal and aerosol routes led to increased shedding, replication and a proinflammatory T-cell profile compared to skin inoculation. Contact transmission was higher from rectally inoculated animals. This suggests that transmission might be sustained by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release.