{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:34:28Z","timestamp":1790354068991,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T00:00:00Z","timestamp":1731715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Primary hemophagocytic lymphohistiocytosis (HLH) is a life\u2010threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic\n                    <jats:italic>PRF1<\/jats:italic>\n                    null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life\u2010threatening\u00a0immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin\u2010deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe\u2013immune cell interactions due to specific pathogen\u2010free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a \u201cwild\u201d microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota (\u2018PKO\u2010Wildlings\u2019) and monitored them for signs of HLH. PKO\u2010Wildlings survived long\u2010term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO\u2010Wildlings. Interestingly, after infection with LCMV, PKO\u2010Wildlings developed an altered HLH pattern. This included lower IFN\u2010\u03b3 serum levels along with improved IFN\u2010\u03b3\u2010driven anemia, but more elevated levels of IL\u201017 and increased liver inflammation compared with PKO\u2010SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host\u2013microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology.\n                  <\/jats:p>","DOI":"10.1002\/eji.202451061","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T07:20:29Z","timestamp":1731741629000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Microbiome Modifies Manifestations of Hemophagocytic Lymphohistiocytosis in Perforin\u2010Deficient Mice"],"prefix":"10.1002","volume":"55","author":[{"given":"Jasmin","family":"Mann","sequence":"first","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solveig","family":"Runge","sequence":"additional","affiliation":[{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"},{"name":"Department of Medicine II, Medical Center\u2010 University of Freiburg, Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Department of Microbiome Research, University Hospital Erlangen Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU)  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schell","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Medical Center\u2010 University of Freiburg, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Gr\u00e4we","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Medical Center\u2010 University of Freiburg, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gudrun","family":"Thoulass","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Lao","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Ammann","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gr\u00fcn","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Berger","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Hild","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplantation Medicine Medical Faculty University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aichele","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6989-8686","authenticated-orcid":false,"given":"Stephan P.","family":"Rosshart","sequence":"additional","affiliation":[{"name":"Department of Medicine II, Medical Center\u2010 University of Freiburg, Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Department of Microbiome Research, University Hospital Erlangen Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU)  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9265-2721","authenticated-orcid":false,"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[{"name":"Institute for Immunodeficiency Center for Chronic Immunodeficiency (CCI), Medical Center\u2010 University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5446.1957"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00855-9"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi076"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.09.005"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21039"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2007.05.001"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00808"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00814-6"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00443367"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-495309"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-10-3413"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V78.11.2918.2918"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27344"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.06.048"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788349"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201948123"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.20.9918-9924.2001"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00375-08"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.159.11.5197"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830251209"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.275"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4RI0718-273R"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17655"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.016"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.12.007"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw4361"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14811"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.022"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.79430"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adf7702"},{"key":"e_1_2_11_32_1","unstructured":"K.Flurkey. Jackson Laboratory. Breeding performance survey females of 35 commonly used strains of JAX Mice. MPD:Jax5. Mouse Phenome Database web resource (RRID:SCR_003212) The Jackson Laboratory Bar Harbor Maine USA.https:\/\/phenome.jax.org[Cited (October 2023)]"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.615661"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019378108"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-017-9128-3"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181dbbb17"},{"key":"e_1_2_11_37_1","article-title":"Laboratory Mice With a Wild Microbiota Generate Strong Allergic Immune Responses","author":"Ma J.","year":"2021","journal-title":"BioRxiv"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.09.033"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep24072"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00426"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00448"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.04.017"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009066"},{"key":"e_1_2_11_44_1","volume-title":"Hepatitis A and Other Associated Hepatobiliary Diseases","author":"Somanath P.","year":"2019"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00592-6"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13140"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0711-5"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159806"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.10.068"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41076"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.12.1314"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0616"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-13009-3"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-0934(91)90018-U"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780471729259.mc14a03s39"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-441139"}],"container-title":["European Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.202451061","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T08:01:05Z","timestamp":1740297665000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/eji.202451061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,16]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1002\/eji.202451061"],"URL":"https:\/\/doi.org\/10.1002\/eji.202451061","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/EJI.202451061\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/EJI.202451061\/v3\/response1","asserted-by":"object"}]},"ISSN":["0014-2980","1521-4141"],"issn-type":[{"value":"0014-2980","type":"print"},{"value":"1521-4141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,16]]},"assertion":[{"value":"2024-02-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202451061"}}