A Novel Role of cGAS-STING Signaling in Enhancing Macrophage Phagocytosis of the Lyme Disease Pathogen 3117

Abstract Description Borrelia burgdorferi (Bb), the causative agent of Lyme disease, is an extracellular spirochete that elicits a type I interferon (IFN-I) response via cGAS-STING (cyclic GMP-AMP synthase-Stimulator of Interferon Genes) signaling. While the role of IFN-I in the development of Lyme arthritis and other Lyme-associated complications is established, its involvement in the early stages of Bb infection remains less understood. This study investigates the role of cGAS-STING signaling in the early immune response to Bb infection. Using flow cytometry, confocal microscopy, and limiting dilution assays, we demonstrate that cGAS-STING signaling is essential for macrophage-mediated phagocytosis and killing of Bb. cGAS-deficient (cGAS-/-) macrophages exhibited significantly impaired bacterial clearance compared to wild-type (WT) cells. IFN-I signaling partially mediates this response, as blocking the IFN-I receptor (IFNαR) decreased phagocytosis and bacterial killing, while IFN-β treatment enhanced these activities. Furthermore, flow cytometry and qPCR analyses demonstrated reduced macrophage infiltration (CD45+CD11b+F4/80+) and elevated Bb DNA levels at the infection site in cGAS-/- mice. Notably, pretreatment of WT mice with a cGAS-STING agonist before infection with Bb significantly improved Bb clearance by enhancing macrophage phagocytosis. These findings highlight cGAS-STING signaling as a critical host defense mechanism and suggest its potential as a preventive target in Lyme disease. Funding Sources R01AI152235, R01AI083640 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)