{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T22:08:05Z","timestamp":1789250885408,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"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. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The COVID-19 pandemic has become a global health crisis, eliciting varying severity in infected individuals. This study aimed to explore the immune profiles between moderate and severe COVID-19 patients experiencing a cytokine storm and their association with mortality. This study highlights the role of PD-1\/PD-L1 and the TIGIT\/CD226\/CD155\/CD112 pathways in COVID-19 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a study using flow cytometry to compare the phenotypic and functional characteristics of peripheral blood mononuclear cells in patients with moderate or severe disease and healthy individuals. Soluble immune checkpoint molecule and ligand levels were measured by Luminex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Severe patients show reduced CD8+ T cell frequency, hyperactivation of CD8+ T, NK and NKT cells with concurrent upregulation of immune checkpoint ligands in monocytes. TIGIT expression by CD8+ T and NK cells and PD-1 by NKT cells suggest a spectrum of immune dysfunction, encompassing both hyperactivation and features of exhaustion. This dual phenomenon likely contributes to the impaired viral clearance and the exacerbation of inflammation characteristic of severe disease. Additionally, the study suggests that increased activation and cytotoxicity of NK cells may be associated with fatal outcomes in severe COVID-19 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings shed light on the intricate immune response regulation in COVID-19, emphasizing the importance of immune checkpoint pathways and activation signatures in disease severity. A novel aspect of this study is that it includes only COVID-19 patients experiencing cytokine storms, allowing for a focused analysis of immune dysregulation during this critical phase of the disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2024.1508423","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T06:39:31Z","timestamp":1734935971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Can there be calm during a cytokine storm? Immune checkpoint pathways affecting the severity of COVID-19 disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Matyas","family":"Meggyes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David U.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildiko","family":"Toth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timoteus","family":"Feik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Peterfalvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Polgar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sipos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Kemeny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Szereday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3044","DOI":"10.3389\/FIMMU.2021.697840\/BIBTEX","article-title":"CD169 defines activated CD14+ monocytes with enhanced CD8+ T cell activation capacity","volume":"12","author":"Affandi","year":"2021","journal-title":"Front. 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Res."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/S41577-020-0308-3","article-title":"COVID-19: immunopathology and its implications for therapy","volume":"20","author":"Cao","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/JCM10020297","article-title":"When does the cytokine storm begin in COVID-19 patients? A quick score to recognize it","volume":"10","author":"Cappanera","year":"2021","journal-title":"J. Clin. Med."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/S41577-020-0402-6","article-title":"T cell responses in patients with COVID-19","volume":"20","author":"Chen","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1172\/JCI137244","article-title":"Clinical and immunological features of severe and moderate coronavirus disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e0377623","DOI":"10.1128\/SPECTRUM.03776-23","article-title":"An observational study investigating soluble immune checkpoints as indicators of severe COVID-19","volume":"12","author":"Cort\u00e9s-Vieyra","year":"2024","journal-title":"Microbiol. Spectr."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"15755","DOI":"10.1038\/S41598-022-20139-1","article-title":"Deep RNA sequencing of intensive care unit patients with COVID-19","volume":"12","author":"Fredericks","year":"2022","journal-title":"Sci. Rep."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"810","DOI":"10.3390\/v16050810","article-title":"A prospective study investigating immune checkpoint molecule and CD39 expression on peripheral blood cells for the prognostication of COVID-19 severity and mortality","volume":"16","author":"Gambichler","year":"2024","journal-title":"Viruses"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"4651","DOI":"10.2147\/JIR.S320685","article-title":"Distinct patterns of blood cytokines beyond a cytokine storm predict mortality in covid-19","volume":"14","author":"Herr","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The cytokine storm and COVID-19","volume":"93","author":"Hu","year":"2021","journal-title":"J. Med. 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Immunol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1126\/SCIENCE.ABC8511","article-title":"Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications","volume":"369","author":"Mathew","year":"2020","journal-title":"Science"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"4694","DOI":"10.1172\/JCI138554","article-title":"Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent","volume":"130","author":"Mazzoni","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s41577-020-0331-4","article-title":"Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages","volume":"20","author":"Merad","year":"","journal-title":"Nat. Rev. Immunol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/s41577-020-0353-y","article-title":"Author correction: pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages","volume":"20","author":"Merad","year":"","journal-title":"Nat. Rev. Immunol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/VIM.2022.0002","article-title":"Dysfunctional state of T cells or exhaustion during chronic viral infections and COVID-19: a review","volume":"35","author":"Mishra","year":"2022","journal-title":"Viral Immunol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.abe1670","article-title":"MAIT cell activation and dynamics associated with COVID-19 disease severity","volume":"5","author":"Parrot","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/J.JMIR.2023.02.003","article-title":"Computed tomography severity score as a predictor of disease severity and mortality in COVID-19 patients: a systematic review and meta-analysis","volume":"54","author":"Prakash","year":"2023","journal-title":"J. Med. Imaging Radiat. Sci."},{"key":"ref28","volume-title":"R: A language and environment for statistical computing","year":"2022"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/J.IMMUNI.2020.12.002","article-title":"PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional in patients with COVID-19","volume":"54","author":"Rha","year":"2021","journal-title":"Immunity"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1615\/CRITREVEUKARYOTGENEEXPR.2021040575","article-title":"PD-L1 overexpression in the lungs of subjects who died from COVID-19: are we on the way to understanding the immune system exhaustion induced by SARS-CoV-2?","volume":"32","author":"Ronchi","year":"2022","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2022.912336","article-title":"Hallmarks of severe COVID-19 pathogenesis: a pas de Deux between viral and host factors","volume":"13","author":"Rovito","year":"2022","journal-title":"Front. Immunol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"819","DOI":"10.3390\/V14040819","article-title":"Intermediate monocytes with PD-L1 and CD62L expression as a possible player in active SARS-CoV-2 infection","volume":"14","author":"Rutkowska","year":"2022","journal-title":"Viruses"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"6290","DOI":"10.1172\/JCI140335","article-title":"COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes","volume":"130","author":"S\u00e1nchez-Cerrillo","year":"2020","journal-title":"J. Clin. 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Immunol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/S41421-020-0168-9","article-title":"Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing","volume":"6","author":"Wen","year":"2020","journal-title":"Cell Discov."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/S41423-020-0401-3","article-title":"Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients","volume":"17","author":"Zheng","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1084\/JEM.20121416","article-title":"PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis","volume":"210","author":"Zinselmeyer","year":"2013","journal-title":"J. Exp. 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