{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T20:46:26Z","timestamp":1772311586993,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0008814","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Infections by schistosomes result in granulomatous lesions around parasite eggs entrapped within the host tissues. The host and parasite determinants of the\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    egg-induced granulomatous response are areas of active investigation. Some studies in mice implicate Tumor Necrosis Factor (TNF) produced in response to the infection whereas others fail to find a role for it. In addition, in the mouse model, the\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>mansoni<\/jats:italic>\n                    secreted egg antigen omega-1 is found to induce granulomas but the underlying mechanism remains unknown. We have recently developed the zebrafish larva as a model to study macrophage recruitment and granuloma formation in response to\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    eggs. Here we use this model to investigate the mechanisms by which TNF and omega-1 shape the early granulomatous response. We find that TNF, specifically signaling through TNF receptor 1, is not required for macrophage recruitment to the egg and granuloma initiation but does mediate granuloma enlargement. In contrast, omega-1 mediates initial macrophage recruitment, with this chemotactic activity being dependent on its RNase activity. Our findings further the understanding of the role of these host- and parasite-derived factors and show that they impact distinct facets of the granulomatous response to the schistosome egg.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0008814","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:45:43Z","timestamp":1611063943000},"page":"e0008814","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tumor Necrosis Factor and Schistosoma mansoni egg antigen omega-1 shape distinct aspects of the early egg-induced granulomatous response"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-4598","authenticated-orcid":true,"given":"Kevin K.","family":"Takaki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6744-148X","authenticated-orcid":true,"given":"Francisco J.","family":"Roca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Schramm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-9268","authenticated-orcid":true,"given":"Ruud H. P.","family":"Wilbers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9411-8883","authenticated-orcid":true,"given":"Wannaporn","family":"Ittiprasert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1765-0002","authenticated-orcid":true,"given":"Paul J.","family":"Brindley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7767-4922","authenticated-orcid":true,"given":"Gabriel","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-0377","authenticated-orcid":true,"given":"Matthew","family":"Berriman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-5533","authenticated-orcid":true,"given":"Lalita","family":"Ramakrishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0280-1800","authenticated-orcid":true,"given":"Antonio J.","family":"Pag\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"issue":"1","key":"pntd.0008814.ref001","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-018-0013-8","article-title":"Schistosomiasis","volume":"4","author":"DP McManus","year":"2018","journal-title":"Nat Rev Dis Primers"},{"issue":"7","key":"pntd.0008814.ref002","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1590\/S0074-02762002000700002","article-title":"Experimental models of Schistosoma mansoni infection","volume":"97","author":"AW Cheever","year":"2002","journal-title":"Mem Inst Oswaldo Cruz"},{"issue":"1","key":"pntd.0008814.ref003","first-page":"1","article-title":"The Pathology of Bilharziasis","volume":"4","author":"HS Hutchison","year":"1928","journal-title":"Am J Pathol"},{"key":"pntd.0008814.ref004","article-title":"Schistosoma mansoni Eggs Modulate the Timing of Granuloma Formation to Promote Transmission","author":"KK Takaki","year":"2020","journal-title":"Cell Host Microbe"},{"issue":"6","key":"pntd.0008814.ref005","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nprot.2013.068","article-title":"Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in zebrafish","volume":"8","author":"K Takaki","year":"2013","journal-title":"Nat Protoc"},{"issue":"6","key":"pntd.0008814.ref006","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S1074-7613(02)00475-2","article-title":"Real-time visualization of mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos","volume":"17","author":"JM Davis","year":"2002","journal-title":"Immunity"},{"issue":"Pt 3","key":"pntd.0008814.ref007","first-page":"329","article-title":"The schistosome egg: development and secretions","volume":"122","author":"PD Ashton","year":"2001","journal-title":"Parasitology"},{"issue":"5","key":"pntd.0008814.ref008","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00427-009-0285-9","article-title":"The embryonic development of Schistosoma mansoni eggs: proposal for a new staging system","volume":"219","author":"AD Jurberg","year":"2009","journal-title":"Dev Genes Evol"},{"issue":"6","key":"pntd.0008814.ref009","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1046\/j.1365-3024.2002.00466.x","article-title":"Chemokine responses in schistosomal antigen-elicited granuloma formation","volume":"24","author":"BC Chiu","year":"2002","journal-title":"Parasite Immunol"},{"issue":"3","key":"pntd.0008814.ref010","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1084\/jem.132.3.488","article-title":"Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs","volume":"132","author":"DL Boros","year":"1970","journal-title":"J Exp Med"},{"issue":"1","key":"pntd.0008814.ref011","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.molbiopara.2006.01.003","article-title":"IPSE\/alpha-1: a major immunogenic component secreted from Schistosoma mansoni eggs","volume":"147","author":"G Schramm","year":"2006","journal-title":"Mol Biochem Parasitol"},{"key":"pntd.0008814.ref012","first-page":"75","article-title":"Antigen Sequestration and Destruction in the Schistosome Pseudotubercle","volume":"45","author":"Lichtenberg. Studies on Granuloma Formation. Iii","year":"1964","journal-title":"Am J Pathol"},{"issue":"6370","key":"pntd.0008814.ref013","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/356604a0","article-title":"Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice","volume":"356","author":"P Amiri","year":"1992","journal-title":"Nature"},{"issue":"5","key":"pntd.0008814.ref014","first-page":"1105","article-title":"Cytokine responses during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Production of Th1 and Th2 cytokines and relative contribution of tumor necrosis factor","volume":"145","author":"SW Chensue","year":"1994","journal-title":"Am J Pathol"},{"issue":"11","key":"pntd.0008814.ref015","doi-asserted-by":"crossref","first-page":"5969","DOI":"10.4049\/jimmunol.154.11.5969","article-title":"Cytokine function during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Local and regional participation of IFN-gamma, IL-10, and TNF","volume":"154","author":"SW Chensue","year":"1995","journal-title":"J Immunol"},{"key":"pntd.0008814.ref016","doi-asserted-by":"crossref","first-page":"5375","DOI":"10.1038\/ncomms6375","article-title":"Omega-1 knockdown in Schistosoma mansoni eggs by lentivirus transduction reduces granuloma size in vivo","volume":"5","author":"J Hagen","year":"2014","journal-title":"Nat Commun"},{"key":"pntd.0008814.ref017","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.41337","article-title":"Programmed genome editing of the omega-1 ribonuclease of the blood fluke, Schistosoma mansoni","volume":"8","author":"W Ittiprasert","year":"2019","journal-title":"Elife"},{"issue":"3","key":"pntd.0008814.ref018","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2013.03.022","article-title":"TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species","volume":"153","author":"FJ Roca","year":"2013","journal-title":"Cell"},{"key":"pntd.0008814.ref019","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.3389\/fimmu.2018.02614","article-title":"Schistosome Eggs Impair Protective Th1\/Th17 Immune Responses Against Salmonella Infection","volume":"9","author":"G Schramm","year":"2018","journal-title":"Front Immunol"},{"key":"pntd.0008814.ref020","doi-asserted-by":"crossref","first-page":"45910","DOI":"10.1038\/srep45910","article-title":"Production and glyco-engineering of immunomodulatory helminth glycoproteins in plants","volume":"7","author":"RH Wilbers","year":"2017","journal-title":"Sci Rep"},{"issue":"10","key":"pntd.0008814.ref021","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1084\/jem.20111381","article-title":"Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor","volume":"209","author":"B Everts","year":"2012","journal-title":"J Exp Med"},{"issue":"8","key":"pntd.0008814.ref022","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1084\/jem.20082460","article-title":"Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses","volume":"206","author":"B Everts","year":"2009","journal-title":"J Exp Med"},{"issue":"1","key":"pntd.0008814.ref023","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.chom.2015.06.008","article-title":"Myeloid Growth Factors Promote Resistance to Mycobacterial Infection by Curtailing Granuloma Necrosis through Macrophage Replenishment","volume":"18","author":"AJ Pagan","year":"2015","journal-title":"Cell Host Microbe"},{"issue":"1","key":"pntd.0008814.ref024","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ijpara.2003.10.010","article-title":"Involvement of TNF in limiting liver pathology and promoting parasite survival during schistosome infection","volume":"34","author":"SJ Davies","year":"2004","journal-title":"Int J Parasitol"},{"issue":"5","key":"pntd.0008814.ref025","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1128\/IAI.67.5.2201-2208.1999","article-title":"Egg laying is delayed but worm fecundity is normal in SCID mice infected with Schistosoma japonicum and S. mansoni with or without recombinant tumor necrosis factor alpha treatment","volume":"67","author":"AW Cheever","year":"1999","journal-title":"Infect Immun"},{"issue":"8","key":"pntd.0008814.ref026","doi-asserted-by":"crossref","first-page":"e1004282","DOI":"10.1371\/journal.ppat.1004282","article-title":"Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis","volume":"10","author":"M Nascimento","year":"2014","journal-title":"PLoS Pathog"},{"issue":"2","key":"pntd.0008814.ref027","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2008.06.011","article-title":"Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death","volume":"29","author":"H Clay","year":"2008","journal-title":"Immunity"},{"issue":"1","key":"pntd.0008814.ref028","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/0035-9203(81)90013-4","article-title":"Identification and partial purification of an antigen (omega 1) from Schistosoma mansoni eggs which is putatively hepatotoxic in T-cell deprived mice","volume":"75","author":"DW Dunne","year":"1981","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"2","key":"pntd.0008814.ref029","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.molbiopara.2007.06.002","article-title":"Proteomic analysis of Schistosoma mansoni egg secretions","volume":"155","author":"CL Cass","year":"2007","journal-title":"Mol Biochem Parasitol"},{"issue":"8","key":"pntd.0008814.ref030","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1084\/jem.20082462","article-title":"The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1)","volume":"206","author":"S Steinfelder","year":"2009","journal-title":"J Exp Med"},{"issue":"1","key":"pntd.0008814.ref031","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.molbiopara.2005.08.003","article-title":"Molecular characterization of omega-1: a hepatotoxic ribonuclease from Schistosoma mansoni eggs","volume":"144","author":"CM Fitzsimmons","year":"2005","journal-title":"Mol Biochem Parasitol"},{"issue":"1","key":"pntd.0008814.ref032","doi-asserted-by":"crossref","first-page":"337","DOI":"10.4049\/jimmunol.163.1.337","article-title":"Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile","volume":"163","author":"D Jankovic","year":"1999","journal-title":"J Immunol"},{"issue":"5","key":"pntd.0008814.ref033","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.4049\/jimmunol.164.5.2585","article-title":"Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent","volume":"164","author":"PG Fallon","year":"2000","journal-title":"J Immunol"},{"issue":"Pt 2","key":"pntd.0008814.ref034","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1017\/S0031182000059503","article-title":"The purification, characterization, serological activity and hepatotoxic properties of two cationic glycoproteins (alpha 1 and omega 1) from Schistosoma mansoni eggs","volume":"103","author":"DW Dunne","year":"1991","journal-title":"Parasitology"},{"issue":"10","key":"pntd.0008814.ref035","doi-asserted-by":"crossref","first-page":"e1368","DOI":"10.1371\/journal.pntd.0001368","article-title":"Proteomic identification of IPSE\/alpha-1 as a major hepatotoxin secreted by Schistosoma mansoni eggs","volume":"5","author":"MH Abdulla","year":"2011","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"pntd.0008814.ref036","doi-asserted-by":"crossref","first-page":"e2005504","DOI":"10.1371\/journal.pbio.2005504","article-title":"Dectin-1\/2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses","volume":"16","author":"MMM Kaisar","year":"2018","journal-title":"PLoS Biol"},{"issue":"3","key":"pntd.0008814.ref037","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/j.1432-1033.1970.tb00955.x","article-title":"A mechanism of the irreversible inactivation of bovine pancreatic ribonuclease by diethylpyrocarbonate. A general reaction of diethylpyrocarbonate. A general reaction of diethylpyrocarbonate with proteins","volume":"13","author":"B Wolf","year":"1970","journal-title":"Eur J Biochem"},{"key":"pntd.0008814.ref038","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S0076-6879(01)41144-X","article-title":"Ribonuclease T2","volume":"341","author":"M Irie","year":"2001","journal-title":"Methods Enzymol"},{"key":"pntd.0008814.ref039","first-page":"411","article-title":"The granuloma in tuberculosis: dynamics of a host-pathogen collusion","volume":"3","author":"S Ehlers","year":"2012","journal-title":"Front Immunol"},{"issue":"1","key":"pntd.0008814.ref040","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrrheum.2015.169","article-title":"TNF biology, pathogenic mechanisms and emerging therapeutic strategies","volume":"12","author":"GD Kalliolias","year":"2016","journal-title":"Nat Rev Rheumatol"},{"issue":"3","key":"pntd.0008814.ref041","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.3390\/cancers3032811","article-title":"Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer","volume":"3","author":"N Mukaida","year":"2011","journal-title":"Cancers (Basel)"},{"issue":"3","key":"pntd.0008814.ref042","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/S0002-9440(10)63189-6","article-title":"The innate pulmonary granuloma: characterization and demonstration of dendritic cell recruitment and function","volume":"164","author":"BC Chiu","year":"2004","journal-title":"Am J Pathol"},{"issue":"4","key":"pntd.0008814.ref043","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1128\/IAI.62.4.1199-1206.1994","article-title":"Tumor necrosis factor as an autocrine and paracrine signal controlling the macrophage secretory response to Candida albicans","volume":"62","author":"E Blasi","year":"1994","journal-title":"Infect Immun"},{"issue":"19","key":"pntd.0008814.ref044","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1101\/gad.244749.114","article-title":"Network dynamics determine the autocrine and paracrine signaling functions of TNF","volume":"28","author":"AB Caldwell","year":"2014","journal-title":"Genes Dev"},{"issue":"4","key":"pntd.0008814.ref045","doi-asserted-by":"crossref","first-page":"994","DOI":"10.4049\/jimmunol.2000372","article-title":"Zebrafish IL-4-like Cytokines and IL-10 Suppress Inflammation but Only IL-10 Is Essential for Gill Homeostasis","volume":"205","author":"F Bottiglione","year":"2020","journal-title":"J Immunol"},{"issue":"4","key":"pntd.0008814.ref046","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.4049\/jimmunol.172.4.2439","article-title":"Parasite antigen-driven basophils are a major source of IL-4 in human filarial infections","volume":"172","author":"E Mitre","year":"2004","journal-title":"J Immunol"},{"key":"pntd.0008814.ref047","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1146\/annurev-immunol-032712-100022","article-title":"The Formation and Function of Granulomas","volume":"36","author":"AJ Pagan","year":"2018","journal-title":"Annu Rev Immunol"},{"issue":"3","key":"pntd.0008814.ref048","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/ni.3655","article-title":"Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression","volume":"18","author":"M Linke","year":"2017","journal-title":"Nat Immunol"},{"issue":"5","key":"pntd.0008814.ref049","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nri3211","article-title":"Revisiting the role of the granuloma in tuberculosis","volume":"12","author":"L Ramakrishnan","year":"2012","journal-title":"Nat Rev Immunol"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0008814","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008814","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T23:01:18Z","timestamp":1697583678000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008814"}},"subtitle":[],"editor":[{"given":"John Pius","family":"Dalton","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,19]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0008814","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.09.29.318105","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,19]]}}}