{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T23:58:04Z","timestamp":1771372684048,"version":"3.50.1"},"posted":{"date-parts":[[2024,8,16]]},"group-title":"Immunology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T00:00:00Z","timestamp":1723766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                  (\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  ), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) of\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  responsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component in\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  culture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown. In this study, we reveal that\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  secretes cyclic-di-adenosine monophosphate (c-di-AMP) as a key extracellular PAMP, inducing the host IFN-I response in macrophages. Using genetically manipulated\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  strains, we demonstrate a requirement of c-di-AMP for stimulating IFN-I response by macrophages\n                  <jats:italic>ex vivo<\/jats:italic>\n                  . Additionally, infecting mice with\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  alongside exogenous c-di-AMP resulted in a markedly increased IFN-I response in mouse tissues. Furthermore, inactivation or inhibition of the host STING signaling pathway significantly reduced the IFN-I response, indicating that c-di-AMP-induced IFN-I production is STING-dependent. Our findings identify c-di-AMP as a crucial PAMP secreted by\n                  <jats:italic>B. burgdorferi<\/jats:italic>\n                  to elicit the host IFN-I response via activation of STING signaling pathway, suggesting that targeting c-di-AMP production could represent a novel therapeutic strategy against Lyme arthritis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SUMMARY<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                    , the bacteria that causes Lyme disease, induces a robust host immune response, including the production of type-I interferon (IFN-I). While this response helps combat the infection, it also contributes to complications such as Lyme arthritis. Our research aimed to identify the specific bacterial component that triggers the IFN-I response. We discovered that\n                    <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                    releases a second messenger molecule, cyclic-di-adenosine monophosphate (c-di-AMP), which is recognized by host immune cells and subsequently triggers IFN-I production. This finding is significant as it advances our understanding of Lyme disease pathogenesis and offers a new strategy to tackle Lyme disease by targeting the production of c-di-AMP, in which we may be able to reduce the severity of the disease and mitigate long-term tissue damage.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                    c-di-AMP induces Type I IFN response\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.13.607721","type":"posted-content","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T20:10:32Z","timestamp":1723839032000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Borrelia burgdorferi<\/i>\n                  Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts"],"prefix":"10.64898","author":[{"given":"Raj","family":"Priya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiping","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sajith","family":"Raghunanadanan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qigui","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongliang","family":"Lou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herman O.","family":"Sintim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-3167","authenticated-orcid":false,"given":"X. 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