Lack of IFN-γ/iNOS signaling leads to skin eschar-like lesion in a scrub typhus mouse model 2727

Description Scrub typhus is an infectious disease caused by the bacterium Orientia tsutsugamushi (Ot), transmitted to humans through infected chigger mites. Severe cases can result in organ failure and hemorrhage, leading to fatality if untreated. The mechanisms by which the host innate immune system responds to this infection remain poorly understood. Using an intradermal (i.d.) inoculation mouse model, we previously reported that the absence of IFN-γ, but not IFN-I signaling, led to the development of visible skin eschar lesions. Inducible nitric oxide synthase (iNOS), a molecule strongly upregulated by IFN-γ, plays a critical role in the host response to bacterial infections. However, its specific role in scrub typhus has not been explored. To address this, we i.d. infected iNOS-/- mice with Ot. While body weight and disease symptoms were similar between wild-type and iNOS-/- mice, the absence of iNOS signaling resulted in pronounced skin eschar-like lesions, resembling those observed in IFN-γ-deficient mice. To determine whether iNOS is essential for bacterial control, we infected wild-type and iNOS-/- bone marrow-derived macrophages (M?) in vitro. The bacterial burden was significantly higher in iNOS-/- M? compared to wild-type M?, regardless of the presence or absence of recombinant IFN-γ. Overall, our findings highlight the critical role of the IFN-γ/iNOS axis in mediating antibacterial responses and in the development of skin eschar-like lesions during scrub typhus infection. Funding Sources NIH-AI132674 UTMB IHII NTT Startup Grant Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)