{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:55:26Z","timestamp":1791064526416,"version":"4.1.0"},"reference-count":90,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH National Center for Research Resources and the National Center for Advancing Translational Sciences","award":["UL1TR001449"],"award-info":[{"award-number":["UL1TR001449"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors\u2019 and decedents\u2019 cases. However, total uPA in decedents\u2019 cases was significantly higher compared to survivors\u2019. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-\u03b3. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.<\/jats:p>","DOI":"10.3390\/v13081597","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T22:14:36Z","timestamp":1628806476000},"page":"1597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Longitudinal Assessment of Cytokine Expression and Plasminogen Activation in Hantavirus Cardiopulmonary Syndrome Reveals Immune Regulatory Dysfunction in End-Stage Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Peter","family":"Simons","sequence":"first","affiliation":[{"name":"Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-3960","authenticated-orcid":false,"given":"Yan","family":"Guo","sequence":"additional","affiliation":[{"name":"Bioinformatics Shared Resource Center, Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Bondu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Tigert","sequence":"additional","affiliation":[{"name":"Clinical and Translational Science Center (CTSC), University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Harkins","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0471-8303","authenticated-orcid":false,"given":"Samuel","family":"Goodfellow","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cana","family":"Tompkins","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6437-8438","authenticated-orcid":false,"given":"Devon","family":"Chabot-Richards","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6816-7024","authenticated-orcid":false,"given":"Xuexian O.","family":"Yang","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7505-4909","authenticated-orcid":false,"given":"Laura Gonzalez","family":"Bosc","sequence":"additional","affiliation":[{"name":"Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Bradfute","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tione","family":"Buranda","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.3390\/v2122559","article-title":"Hantaviruses in the americas and their role as emerging pathogens","volume":"2","author":"Hjelle","year":"2010","journal-title":"Viruses"},{"key":"ref_2","first-page":"552","article-title":"Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease","volume":"146","author":"Zaki","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s10096-016-2592-1","article-title":"Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection","volume":"35","author":"Rasmuson","year":"2016","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.micinf.2006.04.019","article-title":"Hantavirus cardiopulmonary syndrome: Immune response and pathogenesis","volume":"8","author":"Borges","year":"2006","journal-title":"Microbes Infect. Inst. Pasteur"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8279","DOI":"10.1128\/JVI.00742-06","article-title":"Loss of cell membrane integrity in puumala hantavirus-infected patients correlates with levels of epithelial cell apoptosis and perforin","volume":"80","author":"Klingstrom","year":"2006","journal-title":"J. Virol."},{"key":"ref_6","first-page":"222","article-title":"Hantavirus-induced disruption of the endothelial barrier: Neutrophils are on the payroll","volume":"6","author":"Schonrich","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Scholz, S., Baharom, F., Rankin, G., Maleki, K.T., Gupta, S., Vangeti, S., Pourazar, J., Discacciati, A., Hoijer, J., and Bottai, M. (2017). Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006462"},{"key":"ref_8","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":"Morzunov","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.ejcts.2011.01.089","article-title":"Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment","volume":"40","author":"Wernly","year":"2011","journal-title":"Eur. J. Cardio Thorac. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1093\/infdis\/173.6.1297","article-title":"Hantavirus pulmonary syndrome: The first 100 US cases","volume":"173","author":"Khan","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_11","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":"Nolte","year":"1995","journal-title":"Hum. Pathol."},{"key":"ref_12","unstructured":"Hjelle, B. (2019). Epidemiology and Diagnosis of Hantavirus Infections, Wolters Kluwer; UpToDate."},{"key":"ref_13","first-page":"417","article-title":"Dendritic cells as Achilles\u2019 heel and Trojan horse during varicella zoster virus infection","volume":"6","author":"Schonrich","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1084\/jem.20011502","article-title":"Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues","volume":"195","author":"Campbell","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/ni.f.208","article-title":"Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking","volume":"9","author":"Sigmundsdottir","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s12026-009-8105-x","article-title":"Regulation of immunity at tissue sites of inflammation","volume":"45","author":"Sojka","year":"2009","journal-title":"Immunol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/ni.f.213","article-title":"Orchestrating the orchestrators: Chemokines in control of T cell traffic","volume":"9","author":"Bromley","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1084\/jem.20130091","article-title":"Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4","volume":"210","author":"Mikhak","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1086\/314597","article-title":"High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome","volume":"179","author":"Mori","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_20","first-page":"259","article-title":"Hantavirus pulmonary syndrome: Clinical, diagnostic, and virologic aspects","volume":"10","author":"Jenison","year":"1995","journal-title":"Semin. Respir. Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1309\/CNWF-DC72-QYMR-M8DA","article-title":"Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review","volume":"116","author":"Koster","year":"2001","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7114","DOI":"10.1073\/pnas.1401998111","article-title":"Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques","volume":"111","author":"Safronetz","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/nrmicro3066","article-title":"Uncovering the mysteries of hantavirus infections","volume":"11","author":"Vaheri","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1006\/viro.1997.8827","article-title":"Hantavirus pulmonary syndrome: CD8+ and CD4+ cytotoxic T lymphocytes to epitopes on Sin Nombre virus nucleocapsid protein isolated during acute illness","volume":"238","author":"Ennis","year":"1997","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.4049\/jimmunol.172.5.3297","article-title":"Role of specific CD8+ T cells in the severity of a fulminant zoonotic viral hemorrhagic fever, hantavirus pulmonary syndrome","volume":"172","author":"Kilpatrick","year":"2004","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.imlet.2007.08.003","article-title":"Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+ T cells trigger capillary leakage in viral hemorrhagic fevers?","volume":"113","author":"Terajima","year":"2007","journal-title":"Immunol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1128\/JVI.02906-13","article-title":"A lethal disease model for hantavirus pulmonary syndrome in immunosuppressed Syrian hamsters infected with Sin Nombre virus","volume":"88","author":"Brocato","year":"2014","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hammerbeck, C.D., Brocato, R.L., Bell, T.M., Schellhase, C.W., Mraz, S.R., Queen, L.A., and Hooper, J.W. (2016). Depletion of Alveolar macrophages does not prevent hantavirus disease pathogenesis in golden syrian hamsters. J. Virol.","DOI":"10.1128\/JVI.00304-16"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3390\/v7020559","article-title":"Elevated cytokines, thrombin and PAI-1 in severe HCPS Patients due to sin nombre virus","volume":"7","author":"Bondu","year":"2015","journal-title":"Viruses"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/path.3992","article-title":"PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury","volume":"228","author":"Osterholzer","year":"2012","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1111\/j.1538-7836.2011.04377.x","article-title":"Elevated levels of PAI-1 activity and t-PA antigen are associated with newly diagnosed abnormal glucose regulation in patients with ST-elevation myocardial infarction","volume":"9","author":"Knudsen","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"562481","DOI":"10.1155\/2011\/562481","article-title":"PAI-1: An Integrator of cell signaling and migration","volume":"2011","author":"Czekay","year":"2011","journal-title":"Int. J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1111\/j.1538-7836.2005.01420.x","article-title":"PAI-1 and atherothrombosis","volume":"3","author":"Vaughan","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1160\/TH05-01-0033","article-title":"Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease","volume":"93","author":"Dellas","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6986","DOI":"10.1038\/sj.onc.1207859","article-title":"Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth","volume":"23","author":"Bajou","year":"2004","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nrm2821","article-title":"Regulation of cell signalling by uPAR","volume":"11","author":"Smith","year":"2010","journal-title":"Nat. Rev. Mol. Cell. Bio."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fcimb.2018.00169","article-title":"Upregulation of P2Y2R, Active uPA and PAI-1 Are Essential Components of Hantavirus Cardiopulmonary Syndrome","volume":"8","author":"Bondu","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1182\/blood.V69.1.22.22","article-title":"Activation of Plasminogen by single-chain urokinase or by 2-chain urokinase-a demonstration that single-chain urokinase has a low catalytic activity (prourokinase)","volume":"69","author":"Pannell","year":"1987","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1016\/S0021-9258(17)39035-X","article-title":"Proteolytic Cleavage of single-chain pro-urokinase induces conformational change which follows activation of the zymogen and reduction of its high-affinity for fibrin","volume":"260","author":"Kasai","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3545","DOI":"10.1182\/blood.V87.9.3545.bloodjournal8793545","article-title":"Single-chain urokinase-type plasminogen activator bound to its receptor is relatively resistant to plasminogen activator inhibitor type 1","volume":"87","author":"Higazi","year":"1996","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1172\/JCI117114","article-title":"The Urokinase receptor is required for human monocyte chemotaxis in-vitro","volume":"93","author":"Gyetko","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/jlb.51.3.256","article-title":"Urokinase Expression in mononuclear phagocytes-cytokine-specific modulation by interferon-gamma and tumor-necrosis-factor-alpha","volume":"51","author":"Gyetko","year":"1992","journal-title":"J. Leukoc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5539","DOI":"10.4049\/jimmunol.167.10.5539","article-title":"Cutting edge: Antigen-driven lymphocyte recruitment to the lung is diminished in the absence of urokinase-type plasminogen activator (uPA) receptor, but is independent of uPA","volume":"167","author":"Gyetko","year":"2001","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00418-004-0639-3","article-title":"Pericellular proteolysis by leukocytes and tumor cells on substrates: Focal activation and the role of urokinase-type plasminogen activator","volume":"121","author":"Kindzelskii","year":"2004","journal-title":"Histochem. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1182\/blood-2010-03-276642","article-title":"Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation","volume":"116","author":"Connolly","year":"2010","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20032","DOI":"10.1074\/jbc.270.34.20032","article-title":"Interaction of single-chain urokinase and plasminogen activator inhibitor type 1","volume":"270","author":"Manchanda","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1160\/TH02-12-0310","article-title":"Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system","volume":"92","author":"Teesalu","year":"2004","journal-title":"Thromb. Haemost."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10578","DOI":"10.1073\/pnas.180197197","article-title":"Experimental infection model for Sin Nombre hantavirus in the deer mouse (peromyscus maniculatus)","volume":"97","author":"Botten","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"986048","DOI":"10.1155\/2014\/986048","article-title":"Advanced heat map and clustering analysis using heatmap3","volume":"2014","author":"Zhao","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1086\/508494","article-title":"Sin nombre viral RNA load in patients with hantavirus cardiopulmonary syndrome","volume":"194","author":"Xiao","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1086\/315153","article-title":"High levels of viremia in patients with the Hantavirus pulmonary syndrome","volume":"180","author":"Terajima","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ni.3123","article-title":"Control of adaptive immunity by the innate immune system","volume":"16","author":"Iwasaki","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-immunol-030409-101212","article-title":"Differentiation of effector CD4 T cell populations (*)","volume":"28","author":"Zhu","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature06878","article-title":"TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function","volume":"453","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.cell.2011.07.033","article-title":"Control of T(H)17\/T(reg) balance by hypoxia-inducible factor 1","volume":"146","author":"Dang","year":"2011","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/mi.2017.77","article-title":"Epithelial-derived TGF-beta1 acts as a pro-viral factor in the lung during influenza A infection","volume":"11","author":"Denney","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.4049\/jimmunol.126.4.1415","article-title":"Plasminogen activator is an apparent lymphocyte mitogen","volume":"126","author":"Cohen","year":"1981","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1038\/s41598-018-37259-2","article-title":"The prognostic relevance of urokinase-type plasminogen activator (uPA) in the blood of patients with metastatic breast cancer","volume":"9","author":"Witzel","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1055\/s-0038-1646415","article-title":"A kinetic model of the circulatory regulation of tissue plasminogen activator","volume":"66","author":"Chandler","year":"1991","journal-title":"Thromb. Haemost."},{"key":"ref_60","first-page":"492","article-title":"A population-based study in Ghana to investigate inter-individual variation in plasma t-PA and PAI-1","volume":"17","author":"Williams","year":"2007","journal-title":"Ethn. Dis."},{"key":"ref_61","first-page":"1268","article-title":"Cytokine-Specific regulation of urokinase receptor (Cd87) expression by U937 mononuclear phagocytes","volume":"84","author":"Sitrin","year":"1994","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1471-4906(02)00013-3","article-title":"IL-6: A regulator of the transition from neutrophil to monocyte recruitment during inflammation","volume":"24","author":"Kaplanski","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.4049\/jimmunol.175.6.3463","article-title":"Directing transition from innate to acquired immunity: Defining a role for IL-6","volume":"175","author":"Jones","year":"2005","journal-title":"J. Immunol."},{"key":"ref_64","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":"Hunter","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Liu, T., Zhang, L., Joo, D., and Sun, S.C. (2017). NF-kappaB signaling in inflammation. Signal Transduct. Target. Ther., 2.","DOI":"10.1038\/sigtrans.2017.23"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8280","DOI":"10.4049\/jimmunol.175.12.8280","article-title":"IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase\/Akt and MEK\/ERK1\/2 pathways","volume":"175","author":"Yoo","year":"2005","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/imr.12671","article-title":"Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology","volume":"285","author":"Cicchese","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.immuni.2009.05.001","article-title":"Plasticity of CD4+ T cell lineage differentiation","volume":"30","author":"Zhou","year":"2009","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Baker, S.K., and Strickland, S. (2020). A critical role for plasminogen in inflammation. J. Exp. Med., 217.","DOI":"10.1084\/jem.20191865"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/jlb.67.2.149","article-title":"Extracellular matrix moieties, cytokines, and enzymes: Dynamic effects on immune cell behavior and inflammation","volume":"67","author":"Vaday","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2174\/1389203718666171030103801","article-title":"Transforming growth factor-beta and urokinase type plasminogen interplay in cancer","volume":"19","author":"Santibanez","year":"2018","journal-title":"Curr. protein Pept. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Cantrell, D. (2015). Signaling in lymphocyte activation. Cold Spring Harb. Perspect. Biol., 7.","DOI":"10.1101\/cshperspect.a018788"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.it.2004.06.004","article-title":"UPA and uPAR in fibrinolysis, immunity and pathology","volume":"25","author":"Mondino","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fonc.2018.00024","article-title":"Multifaceted Role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): Diagnostic, prognostic and therapeutic applications","volume":"8","author":"Mahmood","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13054-016-1250-4","article-title":"The role of neutrophils in immune dysfunction during severe inflammation","volume":"20","author":"Leliefeld","year":"2016","journal-title":"Crit. Care"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.1007\/s00018-013-1286-4","article-title":"Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: Similarities and differences","volume":"70","author":"Pillay","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.celrep.2018.07.027","article-title":"Interleukin-1beta maturation triggers its relocation to the plasma membrane for gasdermin-d-dependent and -independent secretion","volume":"24","author":"Monteleone","year":"2018","journal-title":"Cell Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.celrep.2014.06.028","article-title":"The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge","volume":"8","author":"Chen","year":"2014","journal-title":"Cell Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1084\/jem.20172222","article-title":"Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity","volume":"215","author":"Boucher","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.cell.2016.03.046","article-title":"Inflammasome complexes: Emerging mechanisms and effector functions","volume":"165","author":"Rathinam","year":"2016","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.mib.2013.02.004","article-title":"Antimicrobial functions of inflammasomes","volume":"16","author":"Chen","year":"2013","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Bryce, C., Grimes, Z., Pujadas, E., Ahuja, S., Beasley, M.B., Albrecht, R., Hernandez, T., Stock, A., Zhao, Z., and AlRasheed, M.R. (2021). Pathophysiology of SARS-CoV-2: The mount sinai COVID-19 autopsy experience. Mod. Pathol.","DOI":"10.1038\/s41379-021-00793-y"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nri.2017.36","article-title":"The immunopathology of sepsis and potential therapeutic targets","volume":"17","author":"Scicluna","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41586-020-2588-y","article-title":"Longitudinal analyses reveal immunological misfiring in severe COVID-19","volume":"584","author":"Lucas","year":"2020","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"22351","DOI":"10.1073\/pnas.2010229117","article-title":"IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome","volume":"117","author":"Kang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1038\/s41598-020-80010-z","article-title":"Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients","volume":"11","author":"Zuo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_88","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":"Maleki","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1038\/s41467-020-17292-4","article-title":"Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia","volume":"11","author":"Meschiari","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"852","DOI":"10.7326\/L20-0681","article-title":"Regulatory T Cells for treating patients with COVID-19 and acute respiratory distress syndrome: Two case reports","volume":"173","author":"Gladstone","year":"2020","journal-title":"Ann. Intern. Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:51Z","timestamp":1760165091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":90,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["v13081597"],"URL":"https:\/\/doi.org\/10.3390\/v13081597","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}