A Humanized IFN-γ Mouse Model Reveals Enhanced Susceptibility and Pathogenesis with Skin Eschar Formation in Scrub Typhus

Scrub typhus, caused by Orientia tsutsugamushi (Ot), is a serious acute febrile illness associated with significant mortality. An estimated one million cases occur annually, with more than one billion people at risk. No effective vaccine is currently available, largely due to the complex 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, 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). Humanized mice exhibited pronounced biochemical abnormalities and tissue pathology accompanied by dysregulated T cell and neutrophil responses following infection. Notably, these immunocompetent mice developed skin eschar-like lesions resembling those observed in human patients. Overall, our study introduces a promising humanized mouse model for dissecting the immunopathogenesis of scrub typhus and evaluating future vaccine candidates.