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

Abstract

Scrub typhus, caused by Orientia tsutsugamushi (Ot) bacteria, 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 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 via mites. Here, we report for the first time that a genetically engineered humanized mouse strain (with triple knockout/knock-in of IFN-{gamma} 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 exhibit pronounced biochemical abnormalities and tissue pathology accompanied by dysregulated T cell and neutrophil responses following infection. Notably, these immunocompetent mice develop skin eschar-like lesions resembling those observed in human patients. Overall, our study introduces a promising humanized mouse model to dissect the immunopathogenesis of scrub typhus and evaluate future vaccine candidates. Author SummaryScrub typhus is a serious disease caused by the obligately intracellular bacterium Ot that spreads to humans through the bite of larval mites called chiggers. It affects over a million people each year, primarily in Asia, and can lead to life-threatening complications. Unfortunately, we still lack a clear understanding of how this infection causes disease, partly because there is not a good laboratory model that closely reflects how humans respond to infection. Our recent reports have suggested an important role of IFN-{gamma} in host protection against Ot infection. In this study, we used a new genetically modified mouse strain that carries human IFN-{gamma} signaling in place of its mouse counterpart. We found that these humanized mice are more vulnerable to infection, develop skin eschar lesions like those in patients, and show signs of systemic inflammation and organ damage. Their immune response also resembled what has been observed in human patients. This new mouse model can help scientists better understand the mechanisms as to how this bacterial species causes severe disease outcomes in patients. Once those mechanisms are understood, this mouse model will serve a further purpose as a tool for testing new vaccines and treatments to aid humans at-risk for scrub typhus.