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However, the specific pathogen-associated molecular pattern (PAMP) driving this response remains unidentified. Previous studies have reported that B. burgdorferi culture supernatants significantly stimulate macrophage IFN-I responses, but the responsible component was unknown. In this study, we identified cyclic-di-adenosine monophosphate (c-di-AMP) as the critical PAMP for the induction of IFN response. Inactivation of cdaA, which encodes diadenylate cyclase for c-di-AMP synthesis, significantly reduced IFN-\u03b2 production in murine macrophage cell lines (RAW264.7) and bone marrow\u2013derived macrophages. Conversely, the deletion of dhhP, which encodes c-di-AMP phosphodiesterase, dramatically increased IFN-\u03b2 production. We further demonstrated that B. burgdorferi releases c-di-AMP, which is the major component in the culture supernatant responsible for stimulating the IFN-I response in macrophages. Furthermore, B. burgdorferi c-di-AMP\u2013induced IFN-I response depends on STING, as inactivation or inhibition of STING signaling markedly reduced IFN-I induction. These findings establish c-di-AMP as a key PAMP of B. burgdorferi that activates host STING signaling to induce IFN-I responses, highlighting its potential as a therapeutic target for Lyme arthritis.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf133","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T01:15:14Z","timestamp":1751591714000},"page":"2325-2337","source":"Crossref","is-referenced-by-count":5,"title":["<i>Borrelia burgdorferi<\/i> c-di-AMP is a key extracellular pathogen-associated molecular pattern to elicit type I interferon responses in mammalian hosts"],"prefix":"10.1093","volume":"214","author":[{"given":"Raj","family":"Priya","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiping","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of 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Medical University , Beijing,","place":["China"]},{"name":"Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qigui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Lou","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman O","family":"Sintim","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X Frank","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, IN,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"2025093003525815700_vkaf133-B1","first-page":"333","article-title":"Lyme disease in humans","volume":"42","author":"Radolf","year":"2021","journal-title":"Curr Issues Mol 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