{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:06:21Z","timestamp":1787612781159,"version":"build-2736575974"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P023541\/1"],"award-info":[{"award-number":["MR\/P023541\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/W018748\/1"],"award-info":[{"award-number":["MR\/W018748\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["105610"],"award-info":[{"award-number":["105610"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/S019324\/1"],"award-info":[{"award-number":["BB\/S019324\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["203128\/Z\/16\/Z"],"award-info":[{"award-number":["203128\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N025989\/1"],"award-info":[{"award-number":["MR\/N025989\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both na\u00efve and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6c\n                    <jats:sup>lo<\/jats:sup>\n                    monocyte populations in infected SOX9 deficient mice only. Infected SOX9\u2013deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and\/or reverse fibrotic disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012928","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T13:59:22Z","timestamp":1749477562000},"page":"e1012928","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["SOX9 plays an essential role in myofibroblast driven hepatic granuloma integrity and parenchymal repair during schistosomiasis-induced liver damage"],"prefix":"10.1371","volume":"21","author":[{"given":"Kim","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2556-3777","authenticated-orcid":true,"given":"Elliot","family":"Jokl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Costain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonn","family":"Cheeseman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Phythian-Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin N.","family":"Couper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9473-9647","authenticated-orcid":true,"given":"Karen","family":"Piper Hanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"issue":"9859","key":"ppat.1012928.ref001","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"T Vos","year":"2012","journal-title":"Lancet"},{"issue":"7","key":"ppat.1012928.ref002","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0002865","article-title":"The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases","volume":"8","author":"PJ Hotez","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"ppat.1012928.ref003","doi-asserted-by":"crossref","first-page":"624178","DOI":"10.3389\/fimmu.2020.624178","article-title":"Immune evasion strategies of schistosomes","volume":"11","author":"JR Hambrook","year":"2020","journal-title":"Front Immunol"},{"key":"ppat.1012928.ref004","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.3389\/fimmu.2018.03042","article-title":"Schistosome egg migration: mechanisms, pathogenesis and host immune responses","volume":"9","author":"AH Costain","year":"2018","journal-title":"Front Immunol"},{"key":"ppat.1012928.ref005","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fimmu.2013.00089","article-title":"The schistosoma granuloma: friend or foe?","volume":"4","author":"E Hams","year":"2013","journal-title":"Front Immunol"},{"key":"ppat.1012928.ref006","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.semcancer.2020.04.008","article-title":"Regulation and function of SOX9 during cartilage development and regeneration","volume":"67","author":"H Song","year":"2020","journal-title":"Semin Cancer Biol"},{"issue":"12","key":"ppat.1012928.ref007","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.15252\/emmm.201707860","article-title":"SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis","volume":"9","author":"VS Athwal","year":"2017","journal-title":"EMBO Mol Med"},{"issue":"20","key":"ppat.1012928.ref008","doi-asserted-by":"crossref","first-page":"14063","DOI":"10.1074\/jbc.M707390200","article-title":"Ectopic SOX9 mediates extracellular matrix deposition characteristic of organ fibrosis","volume":"283","author":"KP Hanley","year":"2008","journal-title":"J Biol Chem"},{"issue":"1","key":"ppat.1012928.ref009","doi-asserted-by":"crossref","first-page":"17905","DOI":"10.1038\/s41598-018-36037-4","article-title":"SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis","volume":"8","author":"VS Athwal","year":"2018","journal-title":"Sci Rep"},{"issue":"1","key":"ppat.1012928.ref010","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/toxsci\/kfaa097","article-title":"A Novel Sox9\/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis","volume":"177","author":"C Wang","year":"2020","journal-title":"Toxicol Sci"},{"issue":"3","key":"ppat.1012928.ref011","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.stemcr.2019.01.010","article-title":"Lineage Tracing Reveals the Bipotency of SOX9+ Hepatocytes during Liver Regeneration","volume":"12","author":"X Han","year":"2019","journal-title":"Stem Cell Reports"},{"key":"ppat.1012928.ref012","doi-asserted-by":"crossref","first-page":"906338","DOI":"10.3389\/fimmu.2022.906338","article-title":"Dynamics of Host Immune Response Development During Schistosoma mansoni Infection","volume":"13","author":"AH Costain","year":"2022","journal-title":"Front Immunol"},{"issue":"5","key":"ppat.1012928.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1012268","article-title":"Winners vs. losers: Schistosoma mansoni intestinal and liver eggs exhibit striking differences in gene expression and immunogenicity","volume":"20","author":"K Peterkov\u00e1","year":"2024","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1012928.ref014","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.4049\/jimmunol.136.3.1093","article-title":"Regulation of granulomatous inflammation in murine schistosomiasis. III. Recruitment of antigen-specific I-J+ T suppressor cells of the granulomatous response by I-J+ soluble suppressor factor","volume":"136","author":"RC Mathew","year":"1986","journal-title":"J Immunol"},{"issue":"12","key":"ppat.1012928.ref015","doi-asserted-by":"crossref","first-page":"6406","DOI":"10.4049\/jimmunol.164.12.6406","article-title":"Il-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis","volume":"164","author":"K Hoffmann","year":"2000","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1012928.ref016","doi-asserted-by":"crossref","DOI":"10.3390\/biology12050694","article-title":"Aif1: function and connection with inflammatory diseases","volume":"12","author":"D De Leon-Oliva","year":"2023","journal-title":"Biol"},{"issue":"3","key":"ppat.1012928.ref017","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1002\/hep.25758","article-title":"Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans","volume":"56","author":"J Pritchett","year":"2012","journal-title":"Hepatology"},{"issue":"2","key":"ppat.1012928.ref018","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/1521-4141(200002)30:2<470::AID-IMMU470>3.0.CO;2-T","article-title":"Elevated type 1, diminished type 2 cytokines and impaired antibody response are associated with hepatotoxicity and mortalities during schistosoma mansoni infection of cd4-depleted mice","volume":"30","author":"P Fallon","year":"2000","journal-title":"Eur J Immunol"},{"issue":"5","key":"ppat.1012928.ref019","doi-asserted-by":"crossref","first-page":"515","DOI":"10.4269\/ajtmh.1997.56.515","article-title":"Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections","volume":"56","author":"DM Karanja","year":"1997","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"ppat.1012928.ref020","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0166-6851(00)00352-2","article-title":"The guanine protein coupled receptor rhodopsin is developmentally regulated in the free-living stages of Schistosoma mansoni","volume":"112","author":"KF Hoffmann","year":"2001","journal-title":"Mol Biochem Parasitol"},{"issue":"1","key":"ppat.1012928.ref021","doi-asserted-by":"crossref","first-page":"7165","DOI":"10.1038\/s41598-020-64158-2","article-title":"Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation","volume":"10","author":"A Alkhani","year":"2020","journal-title":"Sci Rep"},{"issue":"46","key":"ppat.1012928.ref022","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1119964109","article-title":"Differential ly-6c expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis","volume":"109","author":"P Ramachandran","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1012928.ref023","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3389\/fimmu.2017.00475","article-title":"The ST2\/IL-33 Axis in Immune Cells during Inflammatory Diseases","volume":"8","author":"B Griesenauer","year":"2017","journal-title":"Front Immunol"},{"key":"ppat.1012928.ref024","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3389\/fimmu.2020.00146","article-title":"Galectins, Eosinophiles, and Macrophages May Contribute to Schistosoma japonicum Egg-Induced Immunopathology in a Mouse Model","volume":"11","author":"Z Ye","year":"2020","journal-title":"Front Immunol"},{"issue":"1","key":"ppat.1012928.ref025","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13578-023-01104-5","article-title":"Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function","volume":"13","author":"D Qin","year":"2023","journal-title":"Cell Biosci"},{"issue":"1","key":"ppat.1012928.ref026","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"P Bankhead","year":"2017","journal-title":"Sci Rep"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012928","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T13:59:32Z","timestamp":1749477572000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012928"}},"subtitle":[],"editor":[{"given":"Agostinho","family":"Carvalho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,9]]},"references-count":26,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1012928","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.01.23.634445","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,9]]}}}