{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:49:42Z","timestamp":1792604982081,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Although both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we use a combination of <jats:italic>in vitro<\/jats:italic> studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with <jats:italic>in vivo<\/jats:italic> studies in transgenic mice globally expressing human ACE2 and injected with RBD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1241448","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T22:27:26Z","timestamp":1691706446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein"],"prefix":"10.3389","volume":"14","author":[{"given":"Maritza J.","family":"Romero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhupesh","family":"Singla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrg","family":"Hamacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Sridhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auriel S.","family":"Moseley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mobarak A.","family":"Mraheil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Zeitlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trinad","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Csanyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C.","family":"Eaton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02145","article-title":"Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus","volume":"426","author":"Li","year":"2003","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.01.014","article-title":"Regulators of endothelial and epithelial barrier integrity and function in acute lung injury","volume":"77","author":"Lucas","year":"2009","journal-title":"Biochem Pharmacol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202003-0543OC","article-title":"Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study","volume":"201","author":"Du","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1530\/VB-22-0004","article-title":"SARS-CoV-2, platelets, and endothelium: coexistence in space and time, or a pernicious m\u00e9nage \u00e0 trois","volume":"4","author":"Bogdanov","year":"2022","journal-title":"Vasc Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.202008-1026OC","article-title":"COVID-19 versus non-COVID-19 acute respiratory distress syndrome: comparison of demographics, physiologic parameters, inflammatory biomarkers, and clinical outcomes","volume":"18","author":"Bain","year":"2021","journal-title":"Ann Am Thorac Soc"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.019650","article-title":"Coronavirus disease 2019-associated thrombosis and coagulopathy: review of the pathophysiological characteristics and implications for antithrombotic management","volume":"10","author":"Ortega-Paz","year":"2021","journal-title":"J Am Heart Assoc"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101069","article-title":"Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection","volume":"39","author":"Francischetti","year":"2021","journal-title":"EClinicalMedicine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015432","article-title":"Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19","volume":"383","author":"Ackermann","year":"2020","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0343-0.","article-title":"COVID-19: the vasculature unleashed","volume":"20","author":"Teuwen","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrtlng.2023.05.005","article-title":"Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center","volume":"61","author":"Goldberg","year":"2023","journal-title":"Heart Lung."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8671713","article-title":"Endothelial dysfunction, inflammation, and oxidative stress in COVID-19-mechanisms and therapeutic targets","volume":"2021","author":"Fodor","year":"2021","journal-title":"Oxid Med Cell Longev"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1728","article-title":"Impact of the COVID-19 pandemic on invasive pneumococcal disease and risk of pneumococcal coinfection with SARS-CoV-2: prospective national cohort study, England","volume":"72","author":"Amin-Chowdhury","year":"2020","journal-title":"Clin Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiab128.","article-title":"Prevention of Coronavirus Disease 2019 among older adults receiving pneumococcal conjugate vaccine suggests interactions between Streptococcus pneumoniae and Severe Acute Respiratory Syndrome Coronavirus 2 in the respiratory tract","volume":"225","author":"Lewnard","year":"2022","journal-title":"J Infect Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103812","article-title":"Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs","volume":"75","author":"Won","year":"2022","journal-title":"EBioMedicine"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/hvaa213","article-title":"Ultra-sensitive serial profiling of SARS-CoV-2 antigens and antibodies in plasma to understand disease progression in COVID-19 patients with severe disease","volume":"66","author":"Ogata","year":"2020","journal-title":"Clin Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00223.2021","article-title":"The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in K18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells","volume":"321","author":"Colunga Biancatelli","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00771-8","article-title":"The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice","volume":"24","author":"Rhea","year":"2021","journal-title":"Nat Neurosci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01671-21","article-title":"Elevated cytokine levels in plasma of patients with SARS-CoV-2 do not contribute to pulmonary microvascular endothelial permeability","volume":"10","author":"Kovacs-Kasa","year":"2022","journal-title":"Microbiol Spectr."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/science.8303299","article-title":"Mapping the lectin-like activity of tumor necrosis factor","volume":"263","author":"Lucas","year":"1994","journal-title":"Science"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201405-0833OC","article-title":"A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation","volume":"190","author":"Czikora","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.718163","article-title":"The lectin-like domain of TNF increases ENaC open probability through a novel site at the interface between the second transmembrane and C-terminal domains of the \u03b1-subunit","volume":"291","author":"Lucas","year":"2016","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011-0332OC","article-title":"Protein kinase C-\u03b1 and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability","volume":"47","author":"Lucas","year":"2012","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00842","article-title":"Epithelial sodium channel-alpha mediates the protective effect of the TNF-derived TIP peptide in pneumolysin-induced endothelial barrier dysfunction","volume":"8","author":"Czikora","year":"2017","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu428","article-title":"Pneumococcal hydrogen peroxide-induced stress signaling regulates inflammatory genes","volume":"211","author":"Loose","year":"2015","journal-title":"J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90437.2008","article-title":"SARS-CoV proteins decrease levels and activity of human ENaC via activation of distinct PKC isoforms","volume":"296","author":"Ji","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2021.06.005","article-title":"Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins","volume":"120","author":"Grant","year":"2021","journal-title":"Biophys J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-020-05985-9","article-title":"Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target","volume":"46","author":"Zhang","year":"2020","journal-title":"Intensive Care Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.11.017","article-title":"Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE\/ADAM-17: a positive feedback mechanism in the RAS","volume":"66","author":"Patel","year":"2014","journal-title":"J Mol Cell Cardiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318902","article-title":"SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2","volume":"128","author":"Lei","year":"2021","journal-title":"Circ Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/0004563220928361","article-title":"Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2)","author":"Zemlin","year":"2020","journal-title":"Ann Clin Biochem"},{"key":"B35","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.freeradbiomed.2017.03.017","article-title":"Organizers and activators: Cytosolic Nox proteins impacting on vascular function","volume":"109","author":"Schr\u00f6der","year":"2017","journal-title":"Free Radic Biol Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101655","article-title":"Nox2 activation in Covid-19","volume":"36","author":"Violi","year":"2020","journal-title":"Redox Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121075109","article-title":"Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema","volume":"109","author":"Lucas","year":"2012","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.114909","article-title":"Vascular endotheliitis associated with infections: its pathogenetic role and therapeutic implication","volume":"197","author":"Hattori","year":"2022","journal-title":"Biochem Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2021.104303","article-title":"Endothelial injury in COVID-19 and septic patients","volume":"140","author":"Hokama","year":"2022","journal-title":"Microvasc Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2020-001337","article-title":"Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase","volume":"7","author":"DiNicolantonio","year":"2020","journal-title":"Open Heart."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nm1267","article-title":"A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury","volume":"11","author":"Kuba","year":"2005","journal-title":"Nat Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2020-215395","article-title":"Functional respiratory imaging identifies redistribution of pulmonary blood flow in patients with COVID-19","volume":"76","author":"Thillai","year":"2021","journal-title":"Thorax"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.acra.2020.07.019","article-title":"Assessment of small pulmonary blood vessels in COVID-19 patients using HRCT","volume":"27","author":"Lins","year":"2020","journal-title":"Acad Radiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202210-1884LE","article-title":"Dynamic contrast-enhanced MRI demonstrates pulmonary microvascular abnormalities months after SARS-CoV-2 infection","volume":"207","author":"Zhou","year":"2023","journal-title":"Am J Respir Crit Care Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58603","article-title":"SARS-CoV-2 strategically mimics proteolytic activation of human ENaC","volume":"9","author":"Anand","year":"2020","journal-title":"Elife"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00399.2007","article-title":"Defining an inhibitory domain in the alpha-subunit of the epithelial sodium channel","volume":"294","author":"Carattino","year":"2008","journal-title":"Am J Physiol Renal Physiol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00605.2007","article-title":"Single-channel analysis of functional epithelial sodium channel (ENaC) stability at the apical membrane of A6 distal kidney cells","volume":"295","author":"Yu","year":"2008","journal-title":"Am J Physiol Renal Physiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00153.2007","article-title":"Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor-alpha through protein kinase C","volume":"293","author":"Bao","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2022.04.031","article-title":"Conformational ensemble of the TNF-derived peptide solnatide in solution","volume":"20","author":"Martin-Malpartida","year":"2022","journal-title":"Comput Struct Biotechnol J"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.010908.163250","article-title":"The contribution of epithelial sodium channels to alveolar function in health and disease","volume":"71","author":"Eaton","year":"2009","journal-title":"Annu Rev Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01644","article-title":"Cytokine-ion channel interactions in pulmonary inflammation","volume":"8","author":"Hamacher","year":"2018","journal-title":"Front Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.163.6.2004035","article-title":"Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome","volume":"163","author":"Ware","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s13054-017-1795-x","article-title":"Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial","volume":"21","author":"Krenn","year":"2017","journal-title":"Crit Care"},{"key":"B54","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1186\/s13063-022-06182-3","article-title":"Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate to severe ARDS in a randomized, placebo-controlled, double-blind trial: preliminary evaluation of safety and feasibility in light of the COVID-19 pandemic","volume":"23","author":"Schmid","year":"2022","journal-title":"Trials"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00056.2021","article-title":"Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19","volume":"320","author":"Kirilenko","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/function\/zqaa024","article-title":"A pathophysiological model for COVID-19: critical importance of transepithelial sodium transport upon airway infection","volume":"1","author":"Gentzsch","year":"2020","journal-title":"Funct (Oxf)."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.899198","article-title":"Oxidative stress and hyper-inflammation as major drivers of severe COVID-19 and long COVID: implications for the benefit of high-dose intravenous vitamin C","volume":"13","author":"Vollbracht","year":"2022","journal-title":"Front Pharmacol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1089\/ars.2014.5862","article-title":"NOX2 as a target for drug development: indications, possible complications, and progress","volume":"23","author":"Diebold","year":"2015","journal-title":"Antioxid Redox Signal"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1241448\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T22:27:29Z","timestamp":1691706449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1241448\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2023.1241448"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1241448","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]},"article-number":"1241448"}}