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The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Using epidemiological and genetic data from FinnGen and Estonian Biobank, we identify two previously known variants and an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (<jats:italic>SCGB1D2<\/jats:italic>) protein that increases the susceptibility for Lyme disease. Using live <jats:italic>Borrelia burgdorferi (Bb)<\/jats:italic> we find that recombinant reference SCGB1D2 protein inhibits the growth of <jats:italic>Bb<\/jats:italic> in vitro more efficiently than the recombinant protein with\u00a0SCGB1D2 P53L deleterious missense variant. Finally, using an in vivo murine infection model we show that recombinant SCGB1D2 prevents infection by <jats:italic>Borrelia<\/jats:italic> in vivo. Together, these data suggest that <jats:italic>SCGB1D2<\/jats:italic> is a host defense factor present in the skin, sweat, and other secretions which protects against <jats:italic>Bb<\/jats:italic> infection and opens an exciting therapeutic avenue for Lyme disease.<\/jats:p>","DOI":"10.1038\/s41467-024-45983-9","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T11:02:05Z","timestamp":1710846125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["SCGB1D2 inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Satu","family":"Strausz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6529-3161","authenticated-orcid":false,"given":"Erik","family":"Abner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Blacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Galloway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6062-3029","authenticated-orcid":false,"given":"Paige","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingying","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon T.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0153-922X","authenticated-orcid":false,"given":"Samuel E.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hele","family":"Haapaniemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sten","family":"Raak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Ronald","family":"Nahass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"FinnGen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Estonian Genome Centre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Estonian Biobank Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilleriin","family":"Soodla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-1652","authenticated-orcid":false,"given":"Urmo","family":"V\u00f5sa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T\u00f5nu","family":"Esko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-0601","authenticated-orcid":false,"given":"Nasa","family":"Sinnott-Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9077-7467","authenticated-orcid":false,"given":"Irving L.","family":"Weissman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Daly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4285-7179","authenticated-orcid":false,"given":"Tuomas","family":"Aivelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-6246","authenticated-orcid":false,"given":"Michal Caspi","family":"Tal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna M.","family":"Ollila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"45983_CR1","doi-asserted-by":"publisher","first-page":"725","DOI":"10.7326\/0003-4819-107-5-725","volume":"107","author":"AC Steere","year":"1987","unstructured":"Steere, A. 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