A humanized IFN-γ mouse model reveals skin eschar formation, enhanced susceptibility and scrub typhus pathogenesis

Scrub typhus, caused by Orientia tsutsugamushi (Ot) bacteria, is a serious acute febrile illness associated with significant mortality. No effective vaccine is currently available, largely due to the complex Ot strain diversity and an incomplete understanding of protective immune mechanisms. To overcome these challenges, there is a critical need for a suitable animal model that mimics human disease through the natural route of infection. Here, we report for the first time that a genetically engineered humanized mouse strain (with triple knockout/knock-in of IFN-γ and its receptors, abbreviated as hIFNG/hIFNGR), exhibits increased susceptibility to intradermal Ot infection compared to wild-type (WT) mice. This is evidenced by greater body weight loss, elevated bacterial burden, and reduced expression of interferon-stimulated genes (ISGs). hIFNG/hIFNGR mice exhibit pronounced biochemical abnormalities and tissue pathology accompanied by dysregulated T cell and neutrophil responses following infection. Notably, this novel mouse strain with human IFN-γ signaling can develop skin eschar-like lesions resembling those observed in human patients. Overall, our study introduces a promising mouse model to dissect the immunopathogenesis of scrub typhus and evaluate future vaccine candidates.