{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:27:19Z","timestamp":1787318839695,"version":"build-2736575974"},"reference-count":71,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["223103\/Z\/21\/Z"],"award-info":[{"award-number":["223103\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R37 AI054503"],"award-info":[{"award-number":["R37 AI054503"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010071","name":"NWO | Nationaal Regieorgaan Onderwijsonderzoek","doi-asserted-by":"publisher","award":["BBOL-2007247202"],"award-info":[{"award-number":["BBOL-2007247202"]}],"id":[{"id":"10.13039\/501100010071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018956","name":"NIHR | NIHR Cambridge Biomedical Research Centre","doi-asserted-by":"publisher","award":["IS-BRC-1215-20014"],"award-info":[{"award-number":["IS-BRC-1215-20014"]}],"id":[{"id":"10.13039\/501100018956","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,14]]},"abstract":"<jats:p>\n                    Biallelic mutations in the glucocerebrosidase (\n                    <jats:italic>GBA1<\/jats:italic>\n                    ) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation\n                    <jats:italic>GBA1<\/jats:italic>\n                    N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by\n                    <jats:italic>GBA1<\/jats:italic>\n                    N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2217673120","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T15:24:21Z","timestamp":1675697061000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Gaucher disease protects against tuberculosis"],"prefix":"10.1073","volume":"120","author":[{"given":"Jingwen","family":"Fan","sequence":"first","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria L.","family":"Hale","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey T.","family":"Lelieveld","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University 2333 CC, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-4601","authenticated-orcid":false,"given":"Laura J.","family":"Whitworth","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth M.","family":"Busch-Nentwich","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"School of Biological and Behavioral Sciences, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Troll","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4069-5279","authenticated-orcid":false,"given":"Paul H.","family":"Edelstein","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9941","authenticated-orcid":false,"given":"Timothy M.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Roca","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia 30120, Spain"},{"name":"Biomedical Research Institute of Murcia Pascual Parrilla (IMIB-Arrixaca), Murcia 30120, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8168-2565","authenticated-orcid":false,"given":"Johannes M. 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G.","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University 2333 CC, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-5533","authenticated-orcid":false,"given":"Lalita","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK"},{"name":"MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.024"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.14007.1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2020.01.011"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.12.023"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.61722"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024852118"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.02.034"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.022"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201304-0650OC"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.022"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.08.004"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh2841"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu095"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy710"},{"key":"e_1_3_4_15_2","first-page":"1","article-title":"Lysosomal storage diseases","volume":"4","author":"Platt F. 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