{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:13:16Z","timestamp":1778782396439,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,12]]},"group-title":"Immunology","reference-count":20,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"crossref","award":["OFIRG22jul-0081"],"award-info":[{"award-number":["OFIRG22jul-0081"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]},{"name":"A*STAR Graduate Academy","award":["Singapore International Graduate Award (SINGA) scholarship"],"award-info":[{"award-number":["Singapore International Graduate Award (SINGA) scholarship"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["K08GM151392"],"award-info":[{"award-number":["K08GM151392"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cholesterol immunometabolism is a critical controller of immunopathology in respiratory infections such as tuberculosis. Smith-Lemli-Opitz syndrome (SLOS) patients are affected by a loss of 7-dehydrocholesterol reductase (DHCR7) function and have elevated 7-dehydrocholesterol (7DHC) and reduced cholesterol. Increased 7DHC has been found to be protective against viral infections in a range of infection models however SLOS patients have a higher susceptibility to respiratory infection. Here we use the zebrafish-\n                  <jats:italic>Mycobacterium marinum<\/jats:italic>\n                  infection model to demonstrate a compromised innate immune response to bacterial infection in the absence of\n                  <jats:italic>dhcr7<\/jats:italic>\n                  . We correlate increased 7DHC with increased activation of the IRF3\/type I interferon axis and demonstrate Irf3 is a targetable signaling node to restore anti-bacterial immunity in a\n                  <jats:italic>dhcr7<\/jats:italic>\n                  -depleted background.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Plain English summary<\/jats:title>\n                  <jats:p>Loss of 7-dehydrocholesterol reductase causes Smith-Lemli-Opitz syndrome. One of the metabolic features of Smith-Lemli-Opitz syndrome is increased 7-dehydrocholesterol (7DHC). We find increased 7DHC inhibits the ability of zebrafish to control mycobacterial infection by mis-activating an antiviral immune response at the expense of a protective anti-bacterial immune response. Our study suggests the susceptibility to respiratory infections and increased neuroinflammation in Smith-Lemli-Opitz syndrome could be treated by targeting the antiviral protein IRF3.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.07.723652","type":"posted-content","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:50:16Z","timestamp":1778637016000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of 7-Dehydrocholesterol Reductase-mediated cholesterol biosynthesis activates IRF3 and inhibits control of\n                  <i>Mycobacterium marinum<\/i>\n                  infection"],"prefix":"10.64898","author":[{"given":"Xiangyu","family":"Sui","sequence":"first","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore"},{"name":"Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darryl JY","family":"Han","sequence":"additional","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Costa","sequence":"additional","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinitha A","family":"Jacob","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-672X","authenticated-orcid":false,"given":"Stefan H","family":"Oehlers","sequence":"additional","affiliation":[{"name":"A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051410401910000_2026.05.07.723652v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.10"},{"key":"2026051410401910000_2026.05.07.723652v1.2","doi-asserted-by":"crossref","unstructured":"Gabor K , Mesev EV , Madenspacher J , Meacham J , Rai P , Moon S , et al. Sterol biosynthesis regulates TLR signaling and the innate immune response in a Smith-Lemli-Opitz syndrome model. J Clin Invest. 2024;134(6).","DOI":"10.1172\/JCI167633"},{"key":"2026051410401910000_2026.05.07.723652v1.3","doi-asserted-by":"crossref","unstructured":"Freel BA , Kelvington BA , Sengupta S , Mukherjee M , Francis KR . Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk. Dis Model Mech. 2022;15(12).","DOI":"10.1242\/dmm.049843"},{"issue":"1","key":"2026051410401910000_2026.05.07.723652v1.4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.immuni.2019.11.015","article-title":"Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection","volume":"52","year":"2020","journal-title":"Immunity"},{"key":"2026051410401910000_2026.05.07.723652v1.5","doi-asserted-by":"crossref","unstructured":"Chai Q , Lu Z , Zhao M , Yu S , Zhong Y , Qiu C , et al. Lipid accumulation in tuberculosis granulomas inhibits macrophage-CD4(+) T cell interactions and infection control. Nat Microbiol. 2026.","DOI":"10.1038\/s41564-026-02317-3"},{"key":"2026051410401910000_2026.05.07.723652v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.01394"},{"key":"2026051410401910000_2026.05.07.723652v1.7","doi-asserted-by":"crossref","unstructured":"Munson CW , Kaushal D. Type I interferons in tuberculosis pathogenesis and prevention. Trends Microbiol. 2025.","DOI":"10.1016\/j.tim.2025.11.003"},{"issue":"1","key":"2026051410401910000_2026.05.07.723652v1.8","doi-asserted-by":"crossref","first-page":"11635","DOI":"10.1038\/s41598-020-68443-y","article-title":"Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae","volume":"10","year":"2020","journal-title":"Scientific reports"},{"key":"2026051410401910000_2026.05.07.723652v1.9","doi-asserted-by":"crossref","unstructured":"Sima C , Zhang Q , Yu X , Yan B , Zhang S. Metabolic Changes in Zebrafish Larvae Infected with Mycobacterium marinum: A Widely Targeted Metabolomic Analysis. Metabolites. 2025;15(7).","DOI":"10.3390\/metabo15070449"},{"key":"2026051410401910000_2026.05.07.723652v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2018.07.022"},{"key":"2026051410401910000_2026.05.07.723652v1.11","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.fsi.2018.09.037","article-title":"Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility","volume":"83","year":"2018","journal-title":"Fish Shellfish Immunol"},{"issue":"3","key":"2026051410401910000_2026.05.07.723652v1.12","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/infdis\/jiz110","article-title":"Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish","volume":"220","year":"2019","journal-title":"J Infect Dis"},{"key":"2026051410401910000_2026.05.07.723652v1.13","doi-asserted-by":"crossref","unstructured":"Matty MA , Oehlers SH , Tobin DM . Live Imaging of Host\u2013Pathogen Interactions in Zebrafish Larvae. In: Kawakami K , Patton EE , Orger M , editors. Zebrafish: Methods and Protocols. New York, NY: Springer New York; 2016. p. 207\u201323.","DOI":"10.1007\/978-1-4939-3771-4_14"},{"key":"2026051410401910000_2026.05.07.723652v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2018.06.003"},{"key":"2026051410401910000_2026.05.07.723652v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.04.031"},{"key":"2026051410401910000_2026.05.07.723652v1.16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901495"},{"issue":"3","key":"2026051410401910000_2026.05.07.723652v1.17","first-page":"e1225","article-title":"Interferon Regulatory Factor 3 Exacerbates the Severity of COVID-19 in Mice","volume":"7","year":"2025","journal-title":"Crit Care Explor"},{"key":"2026051410401910000_2026.05.07.723652v1.18","doi-asserted-by":"crossref","unstructured":"Tapia VS , Withers SE , Zhou R , Bennington A , Hoyle C , Hedley F , et al. The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation. Dis Model Mech. 2025;18(9).","DOI":"10.1242\/dmm.052145"},{"key":"2026051410401910000_2026.05.07.723652v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.08.003"},{"issue":"6","key":"2026051410401910000_2026.05.07.723652v1.20","first-page":"e0929","article-title":"DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis","volume":"5","year":"2023","journal-title":"Crit Care Explor"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.07.723652","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:40:32Z","timestamp":1778780432000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.07.723652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":20,"URL":"https:\/\/doi.org\/10.64898\/2026.05.07.723652","relation":{},"subject":[],"published":{"date-parts":[[2026,5,12]]},"subtype":"preprint"}}