Borrelia burgdorferi engages mammalian type I interferon responses via the cGAS-STING pathway
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ABSTRACTBorrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multi-system inflammatory disease in humans.B. burgdorferiinfection can lead to Lyme carditis, neurologic complications, and arthritis, due to the ability of specific borrelial strains to disseminate, invade, and drive inflammation.B. burgdorferielicits type I interferon (IFN-I) responses in mammalian cells and tissues that are associated with the development of severe arthritis or other Lyme-related complications. However, the innate immune sensors and signaling pathways controlling IFN-I induction remain unclear. In this study, we examined whether intracellular nucleic acid sensing is required for the induction of IFN-I toB. burgdorferi. Using fluorescence microscopy, we show thatB. burgdorferiassociates with mouse and human cells in culture and we document that internalized spirochetes co-localize with the pattern recognition receptor cyclic GMP-AMP synthase (cGAS). Moreover, we report that IFN-I responses in mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence cGAS or its adaptor Stimulator of Interferon Genes (STING), which function to sense and respond to intracellular DNA. Longitudinal in vivo tracking of bioluminescentB. burgdorferirevealed similar dissemination kinetics and borrelial load in C57BL/6J wild-type, cGAS-deficient, or STING-deficient mice. However, infection-associated tibiotarsal joint pathology and inflammation were modestly reduced in cGAS-deficient compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is a critical mediator of mammalian IFN-I signaling and innate immune responses toB. burgdorferi.KEY POINTSB. burgdorferitriggers type I interferon responses in macrophages and fibroblastsCoiled spirochetes are observed in the cytosol and co-localize with cGAScGAS and STING mediateB. burgdorferi-induced type I interferon responses
