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

作者：Lauren C. Farris, Sylvia Torres-Odio, L. Garry Adams, A. Phillip West, Jenny A. Hyde · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.05.13.491896 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Vector-borne infectious diseases

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, due to 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 fluorescence microscopy, we show that B. burgdorferi associates 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 bioluminescent B. burgdorferi revealed similar dissemination kinetics and borrelial load in C57BL/6J wild-type, cGAS-deficient, or STING-deficient mice. However, infection-assoc...