{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:12:05Z","timestamp":1789164725664,"version":"build-2803163510"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T00:00:00Z","timestamp":1630540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011771","name":"Vascular Medicine Institute, University of Pittsburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011771","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01 HL114453"],"award-info":[{"award-number":["P01 HL114453"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01 HL114453"],"award-info":[{"award-number":["P01 HL114453"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL136143"],"award-info":[{"award-number":["R01 HL136143"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL142084"],"award-info":[{"award-number":["R01 HL142084"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K24 HL143285"],"award-info":[{"award-number":["K24 HL143285"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The Coronavirus Disease 2019 (COVID-19) is caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus that can mediate asymptomatic or fatal infections characterized by pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. Several studies have highlighted the importance of B and T lymphocytes, given that neutralizing antibodies and T cell responses are required for an effective immunity. In addition, other reports have described myeloid cells such as macrophages and monocytes play a major role in the immunity against SARS-CoV-2 as well as dysregulated pro-inflammatory signature that characterizes severe COVID-19. During COVID-19, neutrophils have been defined as a heterogeneous group of cells, functionally linked to severe inflammation and thrombosis triggered by degranulation and NETosis, but also to suppressive phenotypes. The physiological role of suppressive neutrophils during COVID-19 and their implications in severe disease have been poorly studied and is not well understood. Here, we discuss the current evidence regarding the role of neutrophils with suppressive properties such as granulocytic myeloid-derived suppressor cells (G-MDSCs) and their possible role in suppressing CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T lymphocytes expansion and giving rise to lymphopenia in severe COVID-19 infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009850","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T17:26:40Z","timestamp":1630603600000},"page":"e1009850","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Neutrophils and lymphopenia, an unknown axis in severe COVID-19 disease"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1593-678X","authenticated-orcid":true,"given":"Hern\u00e1n 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Hou","year":"2020","journal-title":"Cell"},{"issue":"6","key":"ppat.1009850.ref006","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.chom.2020.04.009","article-title":"Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.","volume":"27","author":"EJ Giamarellos-Bourboulis","year":"2020","journal-title":"Cell Host Microbe."},{"issue":"6","key":"ppat.1009850.ref007","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.chom.2020.05.008","article-title":"Type I and Type III Interferons\u2014Induction, Signaling, Evasion, and Application to Combat COVID-19","volume":"27","author":"A Park","year":"2020","journal-title":"Cell Host Microbe."},{"key":"ppat.1009850.ref008","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cytogfr.2020.04.002","article-title":"Cytokine storm intervention in the early stages of COVID-19 pneumonia","volume":"53","author":"X Sun","year":"2020","journal-title":"Cytokine Growth Factor 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Zhou","year":"2021","journal-title":"Cell"},{"key":"ppat.1009850.ref013","article-title":"Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia","author":"RA Grant","year":"2021","journal-title":"Nature"},{"key":"ppat.1009850.ref014","doi-asserted-by":"crossref","first-page":"550","DOI":"10.3389\/fimmu.2017.00550","article-title":"A Role for Neutrophils in Viral Respiratory Disease","volume":"8","author":"JV Camp","year":"2017","journal-title":"Front Immunol"},{"issue":"6513","key":"ppat.1009850.ref015","doi-asserted-by":"crossref","DOI":"10.1126\/science.aba9301","article-title":"Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection","volume":"370","author":"MS Habibi","year":"2020","journal-title":"Science"},{"key":"ppat.1009850.ref016","article-title":"Lower Respiratory Tract Myeloid Cells Harbor SARS-Cov-2 and Display an Inflammatory Phenotype.","author":"WG Bain","year":"2020","journal-title":"Chest."},{"issue":"11","key":"ppat.1009850.ref017","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1172\/JCI141374","article-title":"Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis","volume":"130","author":"P Skendros","year":"2020","journal-title":"J Clin Invest"},{"issue":"11","key":"ppat.1009850.ref018","article-title":"Neutrophil extracellular traps in COVID-19.","volume":"5","author":"Y Zuo","year":"2020","journal-title":"JCI Insight."},{"issue":"6","key":"ppat.1009850.ref019","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20200652","article-title":"Targeting potential drivers of COVID-19: Neutrophil extracellular traps.","volume":"217","author":"BJ Barnes","year":"2020","journal-title":"J Exp Med"},{"issue":"2","key":"ppat.1009850.ref020","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.immuni.2020.06.005","article-title":"Combinatorial Single-Cell 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Hegde","year":"2021","journal-title":"Immunity"},{"issue":"6","key":"ppat.1009850.ref033","doi-asserted-by":"crossref","DOI":"10.1172\/JCI144734","article-title":"Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity","volume":"131","author":"S Falck-Jones","year":"2021","journal-title":"J Clin Invest"},{"issue":"6","key":"ppat.1009850.ref034","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.cell.2020.08.002","article-title":"Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19","volume":"182","author":"A Silvin","year":"2020","journal-title":"Cell"},{"issue":"6","key":"ppat.1009850.ref035","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.cell.2020.08.001","article-title":"Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment","volume":"182","author":"J Schulte-Schrepping","year":"2020","journal-title":"Cell"},{"issue":"11","key":"ppat.1009850.ref036","doi-asserted-by":"crossref","first-page":"108863","DOI":"10.1016\/j.celrep.2021.108863","article-title":"Metabolic programs define dysfunctional immune responses in severe COVID-19 patients","volume":"34","author":"EA Thompson","year":"2021","journal-title":"Cell Rep."},{"issue":"7","key":"ppat.1009850.ref037","doi-asserted-by":"crossref","first-page":"e1009721","DOI":"10.1371\/journal.ppat.1009721","article-title":"Characterization of low-density granulocytes in COVID-19","volume":"17","author":"LE Cabrera","year":"2021","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1009850.ref038","doi-asserted-by":"crossref","first-page":"5243","DOI":"10.1038\/s41467-020-19080-6","article-title":"Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19","volume":"11","author":"G Carissimo","year":"2020","journal-title":"Nat Commun."},{"issue":"9","key":"ppat.1009850.ref039","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1093\/neuonc\/now034","article-title":"Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8\/9 and arginase and suppress T cell function","volume":"18","author":"PR Gielen","year":"2016","journal-title":"Neuro-Oncology"},{"issue":"7","key":"ppat.1009850.ref040","doi-asserted-by":"crossref","first-page":"4666","DOI":"10.4049\/jimmunol.181.7.4666","article-title":"Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells","volume":"181","author":"P Sinha","year":"2008","journal-title":"J Immunol"},{"issue":"41","key":"ppat.1009850.ref041","doi-asserted-by":"crossref","first-page":"21771","DOI":"10.1074\/jbc.M116.726364","article-title":"Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)\/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells","volume":"291","author":"YF Liu","year":"2016","journal-title":"J Biol Chem"},{"issue":"8","key":"ppat.1009850.ref042","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1158\/2159-8290.CD-19-1355","article-title":"Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner.","volume":"10","author":"D Bayik","year":"2020","journal-title":"Cancer Discov."},{"issue":"10","key":"ppat.1009850.ref043","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/s41419-020-03125-1","article-title":"Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome","volume":"11","author":"A Sacchi","year":"2020","journal-title":"Cell Death Dis."},{"issue":"11","key":"ppat.1009850.ref044","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1038\/s41418-020-0572-6","article-title":"Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19).","volume":"27","author":"C Agrati","year":"2020","journal-title":"Cell Death Differ"},{"issue":"5","key":"ppat.1009850.ref045","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00665-18","article-title":"Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 258 by Enhancing Its Clearance in the Airways","volume":"87","author":"HF Pe\u00f1aloza","year":"2019","journal-title":"Infect Immun"},{"issue":"1","key":"ppat.1009850.ref046","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/mi.2012.62","article-title":"STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia","volume":"6","author":"SL Poe","year":"2013","journal-title":"Mucosal Immunol"},{"key":"ppat.1009850.ref047","doi-asserted-by":"crossref","first-page":"13944","DOI":"10.1038\/ncomms13944","article-title":"The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia","volume":"8","author":"K Chakraborty","year":"2017","journal-title":"Nat Commun"},{"issue":"17","key":"ppat.1009850.ref048","first-page":"e89704","article-title":"Acquired resistance to innate immune clearance promotes Klebsiella pneumoniae ST258 pulmonary infection","volume":"1","author":"D Ahn","year":"2016","journal-title":"JCI Insight"},{"issue":"2","key":"ppat.1009850.ref049","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1165\/rcmb.2018-0021OC","article-title":"The Effects of IFN-lambda on Epithelial Barrier Function Contribute to Klebsiella pneumoniae ST258 Pneumonia","volume":"60","author":"D Ahn","year":"2019","journal-title":"Am J Respir Cell Mol 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Munoz-Fontela","year":"2020","journal-title":"Nature"},{"issue":"2","key":"ppat.1009850.ref056","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.chom.2020.12.016","article-title":"Induction of alarmin S100A8\/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19","volume":"29","author":"Q Guo","year":"2021","journal-title":"Cell Host Microbe."}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009850","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T17:27:32Z","timestamp":1630603652000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009850"}},"subtitle":[],"editor":[{"given":"Thomas 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