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.

恙虫病（Scrub typhus）由恙虫病东方体（Orientia tsutsugamushi, Ot）引起，是一种可导致较高病死率的严重急性发热性疾病。据估算，全球每年发病约100万例，逾10亿人面临感染风险。目前尚无有效疫苗获批，这在很大程度上源于其复杂的毒株多样性以及对保护性免疫机制的认知不足。为克服这些挑战，亟需构建一种可通过自然感染途径模拟人类疾病的理想动物模型。本研究首次报道，一种经基因工程改造的、携带干扰素γ（IFN-γ）及其受体三敲除/敲入的人源化小鼠品系，相较于野生型（WT）小鼠，对皮内感染恙虫病东方体的易感性显著升高。该结论得到以下证据支持：受试小鼠出现更严重的体重下降、更高的细菌载量以及干扰素刺激基因（ISGs）表达水平的降低。感染后，人源化小鼠表现出显著的生化异常与组织病理学改变，同时伴随T细胞与中性粒细胞应答失调。值得注意的是，这些具有免疫活性的小鼠出现了类似人类患者的皮肤焦痂样病变。综上，本研究构建了一款颇具前景的人源化小鼠模型，可用于解析恙虫病的免疫发病机制，并为后续疫苗候选物的评价提供有效支撑。