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B. burgdorferi infection can lead to Lyme carditis, neurologic complications, and arthritis because of the ability of specific borrelial strains to disseminate, invade, and drive inflammation. B. burgdorferi elicits type I IFN (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 colocalize 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 of cGAS or its adaptor stimulator of IFN genes (STING), which function to sense and respond to intracellular DNA. Longitudinal in\u00a0vivo 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-associated tibiotarsal joint pathology and inflammation were modestly reduced in cGAS-deficient compared with wild-type mice. Collectively, these results indicate that the cGAS\u2013STING pathway is a critical mediator of mammalian IFN-I signaling and innate immune responses to B. burgdorferi.<\/jats:p>","DOI":"10.4049\/jimmunol.2200354","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T13:07:59Z","timestamp":1681736879000},"page":"1761-1770","source":"Crossref","is-referenced-by-count":13,"title":["<i>Borrelia burgdorferi<\/i> Engages Mammalian Type I IFN Responses via the cGAS\u2013STING Pathway"],"prefix":"10.1093","volume":"210","author":[{"given":"Lauren C","family":"Farris","sequence":"first","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University , Bryan, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Torres-Odio","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University , Bryan, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-1602","authenticated-orcid":false,"given":"L Garry","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University , College Station, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-6895","authenticated-orcid":false,"given":"A Phillip","family":"West","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University , Bryan, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-9980","authenticated-orcid":false,"given":"Jenny A","family":"Hyde","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, School of Medicine, Texas A&M University , Bryan, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"2025021008055792000_r1","doi-asserted-by":"crossref","first-page":"16090","DOI":"10.1038\/nrdp.2016.90","article-title":"Lyme borreliosis. 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