{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T08:43:33Z","timestamp":1775983413684,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,4]]},"group-title":"Immunology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Leptospira interrogans<\/jats:italic>\n                  is the major causative agent of leptospirosis. Humans, canines and livestock animals are susceptible to\n                  <jats:italic>Leptospira<\/jats:italic>\n                  species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to\n                  <jats:italic>Leptospira<\/jats:italic>\n                  spp. remains poorly defined. We show that\n                  <jats:italic>L. interrogans<\/jats:italic>\n                  induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFN\u03b1\/\u03b2 receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection\n                  <jats:italic>in vivo<\/jats:italic>\n                  suggesting that cGAS-STING-driven type I IFN is required for the host defense against\n                  <jats:italic>L. interrogans<\/jats:italic>\n                  . These findings demonstrate the significance of cGAS-STING-dependent type I IFN signaling in mammalian innate immune responses to\n                  <jats:italic>L. interrogans<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    Leptospirosis is a globally distributed zoonotic disease caused by spirochetes belonging to the genus\n                    <jats:italic>Leptospira<\/jats:italic>\n                    . While humans, livestock, and dogs can develop severe or even fatal illness upon infection, rodents typically serve as asymptomatic reservoir hosts. A defining feature of the leptospiral life cycle is the ability of the pathogen to colonize the kidney in these reservoir host species, leading to prolonged urinary shedding and environmental dissemination. Despite the significant global burden of leptospirosis, the innate immune pathways that detect this pathogen and prevent renal colonization remain poorly understood. In this study we demonstrate that\n                    <jats:italic>L. interrogans<\/jats:italic>\n                    induces a robust type I IFN cytokine response from macrophages. The induction of this type I IFN response is dependent on sensing cytosolic DNA by the cGAS-STING pathway. Using\n                    <jats:italic>in vivo<\/jats:italic>\n                    mouse models of\n                    <jats:italic>L. interrogans<\/jats:italic>\n                    infection we further show that activation of this pathway is required to control bacterial burdens and reduce long-term kidney colonization. This study is the first to demonstrate a critical role for cGAS-STING and type I IFN in controlling\n                    <jats:italic>L. interrogans<\/jats:italic>\n                    infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.02.657349","type":"posted-content","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T12:10:19Z","timestamp":1749039019000},"source":"Crossref","is-referenced-by-count":0,"title":["cGAS-STING dependent type I IFN protects against\n                  <i>Leptospira interrogans<\/i>\n                  renal colonization in mice"],"prefix":"10.64898","author":[{"given":"Suman","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Women\u2019s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Research Service, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA"},{"name":"Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bridget","family":"Ratitong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Women\u2019s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sana","family":"Ismaeel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diogo G.","family":"Valadares","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Women\u2019s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-6895","authenticated-orcid":false,"given":"A. Phillip","family":"West","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagaraj","family":"Kerur","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Stehlik","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Dorfleutner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jargalsaikhan","family":"Dagvadorj","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"Women\u2019s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenifer","family":"Coburn","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"},{"name":"Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea J.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA"},{"name":"F. 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