Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway

Abstract

Borrelia 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. burgdorferi infection can lead to Lyme carditis, neurologic complications, and arthritis, dependent upon the ability of specific borrelial strains to disseminate, invade, and drive inflammation. B. burgdorferi elicits 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 to B. burgdorferi. Using confocal microscopy, we show that B. burgdorferi is taken up by mouse and human cells in culture, indicating a route for intracellular detection. In addition, we report that IFN-I responses in primary mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) or its adaptor Stimulator of Interferon Genes (STING), which function together to sense and respond to intracellular DNA. In vivo tracking of bioluminescent B. burgdorferi during infection of C57BL/6 wild-type, cGAS knockout, or STING deficient mice revealed similar dissemination kinetics and borrelial load. However, tibiotarsal joint pathology and inflammation were reduced in cGAS knockout compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is an innate immune sentinel of B. burgdorferi that plays a key role in the induction of mammalian IFN-I responses.