{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:59:26Z","timestamp":1792900766364,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013042","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010794","name":"Medicinska fakulteten, Ume\u00e5 Universitet","doi-asserted-by":"publisher","award":["RV-579011"],"award-info":[{"award-number":["RV-579011"]}],"id":[{"id":"10.13039\/501100010794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010794","name":"Medicinska fakulteten, Ume\u00e5 Universitet","doi-asserted-by":"publisher","award":["RV-734361"],"award-info":[{"award-number":["RV-734361"]}],"id":[{"id":"10.13039\/501100010794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010794","name":"Medicinska fakulteten, Ume\u00e5 Universitet","doi-asserted-by":"publisher","award":["RV-965866"],"award-info":[{"award-number":["RV-965866"]}],"id":[{"id":"10.13039\/501100010794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","award":["20170334 and 20150752"],"award-info":[{"award-number":["20170334 and 20150752"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2024-02578"],"award-info":[{"award-number":["2024-02578"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018713","name":"Center for Innovative Medicine","doi-asserted-by":"publisher","award":["2020-0141"],"award-info":[{"award-number":["2020-0141"]}],"id":[{"id":"10.13039\/501100018713","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:sec id=\"sec020\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS\/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec021\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Effects of IL-6 trans-signaling during\n                      <jats:italic>in vitro<\/jats:italic>\n                      hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec022\">\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      , sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R\/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R\/sgp130 ratio compared to patients that did not.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec023\">\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.ppat.1013042","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T13:39:42Z","timestamp":1744205982000},"page":"e1013042","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS"],"prefix":"10.1371","volume":"21","author":[{"given":"Kimia T.","family":"Maleki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Niemetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda","family":"Christ","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Wigren Bystr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Therese","family":"Thunberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clas","family":"Ahlm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9076-1441","authenticated-orcid":true,"given":"Jonas","family":"Klingstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"ppat.1013042.ref001","doi-asserted-by":"crossref","first-page":"001975","DOI":"10.1099\/jgv.0.001975","article-title":"ICTV virus taxonomy profile: Hantaviridae 2024","volume":"105","author":"SB Bradfute","year":"2024","journal-title":"J Gen Virol"},{"key":"ppat.1013042.ref002","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/joim.12876","article-title":"Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes","volume":"285","author":"J Klingstr\u00f6m","year":"2019","journal-title":"J Inter Med"},{"issue":"9","key":"ppat.1013042.ref003","doi-asserted-by":"crossref","first-page":"e371","DOI":"10.1016\/S1473-3099(23)00128-7","article-title":"Hantavirus in humans: a review of clinical aspects and management","volume":"23","author":"PA Vial","year":"2023","journal-title":"Lancet Infect Dis"},{"key":"ppat.1013042.ref004","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1186\/1471-2334-13-501","article-title":"Cardiopulmonary involvement in Puumala hantavirus infection","volume":"13","author":"J Rasmuson","year":"2013","journal-title":"BMC Infect Dis"},{"key":"ppat.1013042.ref005","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41598-018-37446-1","article-title":"Orthohantaviruses belonging to three phylogroups all inhibit apoptosis in infected target cells","volume":"9","author":"C Sol\u00e0-Riera","year":"2019","journal-title":"Scientific Reports"},{"issue":"2","key":"ppat.1013042.ref006","doi-asserted-by":"crossref","first-page":"e1008297","DOI":"10.1371\/journal.ppat.1008297","article-title":"Hantavirus inhibits apoptosis by preventing mitochondrial membrane potential loss through up-regulation of the pro-survival factor BCL-2","volume":"16","author":"C Sol\u00e0-Riera","year":"2020","journal-title":"PLoS Pathog"},{"issue":"11","key":"ppat.1013042.ref007","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1093\/infdis\/jiz005","article-title":"Serum Markers Associated with Severity and Outcome of Hantavirus Pulmonary Syndrome","volume":"219","author":"KT Maleki","year":"2019","journal-title":"J Infect Dis"},{"issue":"1","key":"ppat.1013042.ref008","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/infdis\/173.1.38","article-title":"Elevated plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, and IL-10 in patients with hemorrhagic fever with renal syndrome","volume":"173","author":"M Linderholm","year":"1996","journal-title":"J Infect Dis"},{"key":"ppat.1013042.ref009","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fimmu.2015.00432","article-title":"Multiplex Analysis of Serum Cytokines in Humans with Hantavirus Pulmonary Syndrome","volume":"6","author":"SP Morzunov","year":"2015","journal-title":"Front Immunol"},{"key":"ppat.1013042.ref010","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/1471-2334-11-142","article-title":"Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome","volume":"11","author":"A Saksida","year":"2011","journal-title":"BMC Infect Dis"},{"key":"ppat.1013042.ref011","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1471-2172-12-65","article-title":"Cytokine expression during early and late phase of acute Puumala hantavirus infection","volume":"12","author":"M Sadeghi","year":"2011","journal-title":"BMC Immunol"},{"issue":"7","key":"ppat.1013042.ref012","doi-asserted-by":"crossref","first-page":"e0005757","DOI":"10.1371\/journal.pntd.0005757","article-title":"Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus","volume":"11","author":"J Angulo","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"ppat.1013042.ref013","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/1471-2334-10-132","article-title":"The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations","volume":"10","author":"TK Outinen","year":"2010","journal-title":"BMC Infect Dis"},{"issue":"5","key":"ppat.1013042.ref014","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/ni.3153","article-title":"IL-6 as a keystone cytokine in health and disease","volume":"16","author":"CA Hunter","year":"2015","journal-title":"Nat Immunol"},{"issue":"9","key":"ppat.1013042.ref015","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.7150\/ijbs.4989","article-title":"IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6","volume":"8","author":"S Rose-John","year":"2012","journal-title":"Int J Biol Sci"},{"key":"ppat.1013042.ref016","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/eji.1830230226","article-title":"The soluble interleukin-6 receptor is generated by shedding","volume":"23","author":"J M\u00fclberg","year":"1993","journal-title":"Eur J Immunol"},{"key":"ppat.1013042.ref017","doi-asserted-by":"crossref","first-page":"6762","DOI":"10.1074\/jbc.RA117.001163","article-title":"The balance of interleukin (IL)-6, IL-6 soluble IL-6 receptor (sIL-6R), and IL-6 sIL-6R sgp130 complexes allows simultaneous classic and trans-signaling","volume":"293","author":"P Baran","year":"2018","journal-title":"J Biol Chem"},{"issue":"10","key":"ppat.1013042.ref018","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41577-023-00856-y","article-title":"Targeting IL-6 trans-signalling: past, present and future prospects","volume":"23","author":"S Rose-John","year":"2023","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"ppat.1013042.ref019","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1182\/blood.V82.4.1120.1120","article-title":"Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130","volume":"82","author":"M Narazaki","year":"1993","journal-title":"Blood"},{"issue":"1","key":"ppat.1013042.ref020","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/j.1749-6632.1989.tb24030.x","article-title":"Human Endothelial Cells Produce IL\u20106. Lack of responses to exogenous IL-6","volume":"557","author":"TJ Podor","year":"1989","journal-title":"Ann N Y Acad Sci"},{"issue":"6","key":"ppat.1013042.ref021","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1172\/JCI119821","article-title":"Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor alpha","volume":"100","author":"V Modur","year":"1997","journal-title":"J Clin Invest"},{"issue":"3","key":"ppat.1013042.ref022","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S1074-7613(00)80334-9","article-title":"Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment","volume":"6","author":"M Romano","year":"1997","journal-title":"Immunity"},{"issue":"4","key":"ppat.1013042.ref023","doi-asserted-by":"crossref","first-page":"C554","DOI":"10.1152\/ajpcell.00323.2020","article-title":"Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells","volume":"320","author":"A Montgomery","year":"2021","journal-title":"Am J Physiol Cell Physiol"},{"issue":"6","key":"ppat.1013042.ref024","doi-asserted-by":"crossref","first-page":"e100646","DOI":"10.1371\/journal.ppat.1006462","article-title":"Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways","volume":"13","author":"S Scholz","year":"2017","journal-title":"PLoS Pathog"},{"key":"ppat.1013042.ref025","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1128\/JVI.00415-07","article-title":"Lambda interferon (IFN-lambda) in serum is decreased in hantavirus-infected patients, and in vitro established infection is insensitive to treatment with all IFNs and inhibits IFN-gamma-induced nitric oxide production","volume":"81","author":"M Stoltz","year":"2007","journal-title":"J Virol"},{"issue":"3","key":"ppat.1013042.ref026","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00296-009-0953-0","article-title":"Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule","volume":"30","author":"M Suzuki","year":"2010","journal-title":"Rheumatol Int"},{"issue":"1","key":"ppat.1013042.ref027","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1046\/j.1365-2249.1996.d01-717.x","article-title":"IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes","volume":"105","author":"C Watson","year":"1996","journal-title":"Clin Exp Immunol"},{"key":"ppat.1013042.ref028","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.exer.2018.09.009","article-title":"Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells","volume":"178","author":"ML Valle","year":"2019","journal-title":"Exp Eye Res"},{"issue":"1","key":"ppat.1013042.ref029","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s11373-004-8170-z","article-title":"ICAM-1 induction by TNFalpha and IL-6 is mediated by distinct pathways via Rac in endothelial cells","volume":"12","author":"BS Wung","year":"2005","journal-title":"J Biomed Sci"},{"issue":"1","key":"ppat.1013042.ref030","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1084\/jem.20100762","article-title":"Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus","volume":"208","author":"NK Bj\u00f6rkstr\u00f6m","year":"2011","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1013042.ref031","doi-asserted-by":"crossref","first-page":"e93810","DOI":"10.1371\/journal.pone.0093810","article-title":"Involvement of the Akt\/NF-\u03baB pathways in the HTNV-mediated increase of IL-6, CCL5, ICAM-1, and VCAM-1 in HUVECs","volume":"9","author":"H Yu","year":"2014","journal-title":"PLoS One"},{"issue":"7","key":"ppat.1013042.ref032","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s00705-004-0306-y","article-title":"Modification of endothelial cell functions by Hantaan virus infection: prolonged hyper-permeability induced by TNF-alpha of hantaan virus-infected endothelial cell monolayers","volume":"149","author":"M Niikura","year":"2004","journal-title":"Arch Virol"},{"issue":"5","key":"ppat.1013042.ref033","doi-asserted-by":"crossref","first-page":"C589","DOI":"10.1152\/ajpcell.00235.2017","article-title":"Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis","volume":"314","author":"H Alsaffar","year":"2018","journal-title":"Am J Physiol Cell Physiol"},{"issue":"1","key":"ppat.1013042.ref034","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.virol.2008.07.002","article-title":"Hantaan virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon, interleukin-6 and tumor necrosis factor-alpha","volume":"380","author":"H Jiang","year":"2008","journal-title":"Virology"},{"key":"ppat.1013042.ref035","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.3389\/fmicb.2016.01077","article-title":"Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner","volume":"7","author":"SF Khaiboullina","year":"2016","journal-title":"Front Microbiol"},{"issue":"1","key":"ppat.1013042.ref036","doi-asserted-by":"crossref","first-page":"ofu027","DOI":"10.1093\/ofid\/ofu027","article-title":"Endothelial activation and repair during hantavirus infection: association with disease outcome","volume":"1","author":"A-M Connolly-Andersen","year":"2014","journal-title":"Open Forum Infect Dis"},{"key":"ppat.1013042.ref037","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1073\/pnas.91.9.3652","article-title":"Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant","volume":"91","author":"M Carr","year":"1994","journal-title":"Proc Natil Acad Sci USA"},{"key":"ppat.1013042.ref038","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.3389\/fimmu.2019.02759","article-title":"More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis","volume":"10","author":"M Gschwandtner","year":"2019","journal-title":"Front Immunol"},{"key":"ppat.1013042.ref039","doi-asserted-by":"crossref","first-page":"e32532","DOI":"10.7554\/eLife.32532","article-title":"C\/EBP\u03b4 drives interactions between human MAIT cells and endothelial cells that are important for extravasation","volume":"7","author":"CH Lee","year":"2018","journal-title":"Elife"},{"issue":"2","key":"ppat.1013042.ref040","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1158\/0008-5472.CAN-10-1496","article-title":"IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer","volume":"71","author":"C-W Lo","year":"2011","journal-title":"Cancer Res"},{"issue":"14","key":"ppat.1013042.ref041","doi-asserted-by":"crossref","first-page":"7405","DOI":"10.1128\/JVI.00576-10","article-title":"Pathogenic hantaviruses Andes virus and Hantaan virus induce adherens junction disassembly by directing vascular endothelial cadherin internalization in human endothelial cells","volume":"84","author":"E Gorbunova","year":"2010","journal-title":"J Virol"},{"issue":"21","key":"ppat.1013042.ref042","doi-asserted-by":"crossref","first-page":"11227","DOI":"10.1128\/JVI.01405-10","article-title":"Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin","volume":"84","author":"P Shrivastava-Ranjan","year":"2010","journal-title":"J Virol"},{"issue":"8","key":"ppat.1013042.ref043","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.4049\/jimmunol.163.8.4583","article-title":"Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor","volume":"163","author":"M Klouche","year":"1999","journal-title":"J Immunol"},{"issue":"5","key":"ppat.1013042.ref044","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bbamcr.2011.01.034","article-title":"The pro- and anti-inflammatory properties of the cytokine interleukin-6","author":"J Scheller","year":"2011","journal-title":"Biochim Biophys Acta"},{"issue":"2","key":"ppat.1013042.ref045","doi-asserted-by":"crossref","first-page":"E411","DOI":"10.1152\/ajpendo.00166.2019","article-title":"The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes","volume":"317","author":"S Aparicio-Siegmund","year":"2019","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"2","key":"ppat.1013042.ref046","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1161\/ATVBAHA.111.229435","article-title":"Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice","volume":"32","author":"H Schuett","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"ppat.1013042.ref047","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.atherosclerosis.2017.09.002","article-title":"Circulating levels of sgp130 and sex hormones in male patients with coronary atherosclerotic disease","volume":"266","author":"Y Cui","year":"2017","journal-title":"Atherosclerosis"},{"issue":"6","key":"ppat.1013042.ref048","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1080\/1354750X.2018.1458151","article-title":"Soluble glycoprotein 130 is inversely related to severity of coronary atherosclerosis","volume":"23","author":"AA Korotaeva","year":"2018","journal-title":"Biomarkers"},{"issue":"2","key":"ppat.1013042.ref049","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.atherosclerosis.2015.04.014","article-title":"Circulating levels of interleukin 6 soluble receptor and its natural antagonist, sgp130, and the risk of myocardial infarction","volume":"240","author":"I Moreno Vel\u00e1squez","year":"2015","journal-title":"Atherosclerosis"},{"issue":"2","key":"ppat.1013042.ref050","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10456-010-9170-4","article-title":"Visualizing vascular permeability and lymphatic drainage using labeled serum albumin","volume":"13","author":"K Vandoorne","year":"2010","journal-title":"Angiogenesis"},{"key":"ppat.1013042.ref051","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/joim.13208","article-title":"Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage","volume":"289","author":"M Wu","year":"2021","journal-title":"Journal of Internal Medicine"},{"issue":"1","key":"ppat.1013042.ref052","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/0046-8177(95)90123-X","article-title":"Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent","volume":"26","author":"KB Nolte","year":"1995","journal-title":"Hum Pathol"},{"key":"ppat.1013042.ref053","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2214\/ajr.178.1.1780159","article-title":"Radiographic findings in 20 patients with hantavirus pulmonary syndrome correlated with clinical outcome","volume":"178","author":"M Boroja","year":"n.d","journal-title":"Am J Roentgenol"},{"issue":"14","key":"ppat.1013042.ref054","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1056\/NEJM199404073301401","article-title":"Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group","volume":"330","author":"JS Duchin","year":"1994","journal-title":"N Engl J Med"},{"issue":"1","key":"ppat.1013042.ref055","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.smim.2014.01.009","article-title":"A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy","volume":"26","author":"T Tanaka","year":"2014","journal-title":"Semin Immunol"},{"key":"ppat.1013042.ref056","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1056\/NEJMoa2100433","article-title":"Interleukin-6 receptor antagonists in critically ill patients with Covid-19","volume":"384","author":"REMAP-CAP Investigators","year":"2021","journal-title":"New England Journal of Medicine"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013042","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013042","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T13:59:41Z","timestamp":1746539981000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013042"}},"subtitle":[],"editor":[{"given":"David","family":"Safronetz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,9]]},"references-count":56,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013042","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.08.15.24312051","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,9]]}}}