{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:55:56Z","timestamp":1780102556198,"version":"3.54.0"},"reference-count":87,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic \u201ccytokine storm\u201d. Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies.<\/jats:p>","DOI":"10.3390\/v15010104","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:14:28Z","timestamp":1672370068000},"page":"104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Counterintuitive Neutrophil-Mediated Pattern in COVID-19 Patients Revealed through Transcriptomics Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Melih","family":"\u00d6zbek","sequence":"first","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7827-1546","authenticated-orcid":false,"given":"Halil Ibrahim","family":"Toy","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0269-6625","authenticated-orcid":false,"given":"I\u015fil","family":"Takan","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyedehsadaf","family":"Asfa","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Arshinchi Bonab","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6706-1375","authenticated-orcid":false,"given":"G\u00f6khan","family":"Karak\u00fclah","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiota I.","family":"Kontou","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University of Thessaly, 35131 Lamia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1227-5274","authenticated-orcid":false,"given":"Styliani A.","family":"Geronikolou","sequence":"additional","affiliation":[{"name":"Clinical, Translational and Experimental Surgery Research Centre, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece"},{"name":"University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children\u2019s Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-3808","authenticated-orcid":false,"given":"Athanasia","family":"Pavlopoulou","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center, Balcova, Izmir 35340, Turkey"},{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University, Balcova, Izmir 35220, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/s12931-020-01479-w","article-title":"From SARS and MERS to COVID-19: A brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses","volume":"21","author":"Zhu","year":"2020","journal-title":"Respir. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1111\/all.15416","article-title":"Presentation of airway and general symptoms in COVID-19 caused by dominant SARS-CoV-2 variants: A follow-up on ARIA consensus","volume":"77","author":"Hagemann","year":"2022","journal-title":"Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S2213-2600(21)00381-7","article-title":"COVID-19-related ARDS: One disease, two trajectories, and several unanswered questions","volume":"9","author":"Lascarrou","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/MCC.0000000000000911","article-title":"Pathophysiology of coronavirus-19 disease acute lung injury","volume":"28","author":"Camporota","year":"2022","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1002\/cbin.11403","article-title":"Lymphopenia in COVID-19: Therapeutic opportunities","volume":"44","author":"Fathi","year":"2020","journal-title":"Cell Biol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"652470","DOI":"10.3389\/fimmu.2021.652470","article-title":"Neutrophils in COVID-19","volume":"12","author":"Reusch","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"593223","DOI":"10.3389\/fphys.2021.593223","article-title":"Pathogenesis of Multiple Organ Injury in COVID-19 and Potential Therapeutic Strategies","volume":"12","author":"Silva","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10735-020-09915-3","article-title":"COVID-19 and multiorgan failure: A narrative review on potential mechanisms","volume":"51","author":"Mokhtari","year":"2020","journal-title":"J. Mol. Histol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.3906\/sag-2108-239","article-title":"COVID-19 and Sepsis","volume":"51","author":"Kayaaslan","year":"2021","journal-title":"Turk. J. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41590-021-00901-9","article-title":"Lessons learned: New insights on the role of cytokines in COVID-19","volume":"22","author":"Buszko","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1093\/eurheartj\/ehaa1005","article-title":"COVID-19: In the eye of the cytokine storm","volume":"42","author":"Liuzzo","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"2003006","DOI":"10.1183\/13993003.03006-2020","article-title":"Confronting the controversy: Interleukin-6 and the COVID-19 cytokine storm syndrome","volume":"56","author":"Chen","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"613422","DOI":"10.3389\/fimmu.2021.613422","article-title":"Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia","volume":"12","author":"Oliveira","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1007\/s12291-021-00989-8","article-title":"Interleukin-6 Perpetrator of the COVID-19 Cytokine Storm","volume":"36","author":"Shekhawat","year":"2021","journal-title":"Indian J. Clin.Biochem. IJCB"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ijmm.2022.5090","article-title":"Thrombocytopenia in COVID-19 and vaccine-induced thrombotic thrombocytopenia","volume":"49","author":"Geronikolou","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"o922","DOI":"10.1136\/bmj.o922","article-title":"COVID-19: Symptomatic infection with omicron variant is milder and shorter than with delta, study reports","volume":"377","author":"Wise","year":"2022","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/S0140-6736(22)00056-3","article-title":"Omicron severity: Milder but not mild","volume":"399","author":"Nealon","year":"2022","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41586-022-04865-0","article-title":"Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination","volume":"607","author":"Suryawanshi","year":"2022","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1038\/s41591-021-01500-9","article-title":"Calming the cytokine storm in COVID-19","volume":"27","author":"Cron","year":"2021","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41392-021-00679-0","article-title":"The signal pathways and treatment of cytokine storm in COVID-19","volume":"6","author":"Yang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.chom.2020.03.021","article-title":"A Dynamic Immune Response Shapes COVID-19 Progression","volume":"27","author":"Ong","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6319","DOI":"10.1038\/s41467-020-20139-7","article-title":"Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection","volume":"11","author":"Desai","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e65508","DOI":"10.7554\/eLife.65508","article-title":"Seroconversion stages COVID-19 into distinct pathophysiological states","volume":"10","author":"Galbraith","year":"2021","journal-title":"Elife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for functional genomics data sets--update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-1-4939-3578-9_5","article-title":"The Gene Expression Omnibus Database","volume":"1418","author":"Clough","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13742-015-0064-7","article-title":"Investigation into the annotation of protocol sequencing steps in the sequence read archive","volume":"4","author":"Alnasir","year":"2015","journal-title":"GigaScience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D939","DOI":"10.1093\/nar\/gkaa980","article-title":"Genenames.org: The HGNC and VGNC resources in 2021","volume":"49","author":"Tweedie","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Society. Ser. B"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.febslet.2004.07.055","article-title":"Rank products: A simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments","volume":"573","author":"Breitling","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1142\/S0219720005001442","article-title":"Rank-based methods as a non-parametric alternative of the T-statistic for the analysis of biological microarray data","volume":"3","author":"Breitling","year":"2005","journal-title":"J. Bioinform. Comput. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Heskes, T., Eisinga, R., and Breitling, R. (2014). A fast algorithm for determining bounds and accurate approximate p-values of the rank product statistic for replicate experiments. BMC Bioinform., 15.","DOI":"10.1186\/s12859-014-0367-1"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Farrel, A., and Guo, J.T. (2017). An efficient algorithm for improving structure-based prediction of transcription factor binding sites. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1755-0"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3414\/ME13-01-0122","article-title":"The evolution of boosting algorithms. From machine learning to statistical modelling","volume":"53","author":"Mayr","year":"2014","journal-title":"Methods Inf. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1088\/1742-6596\/1142\/1\/012012","article-title":"Machine Learning from Theory to Algorithms: An Overview","volume":"1142","author":"Alzubi","year":"2018","journal-title":"J.Phys. Conf. Ser."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-62703-721-1_3","article-title":"Functional annotation of differentially regulated gene set using WebGestalt: A gene set predictive of response to ipilimumab in tumor biopsies","volume":"1101","author":"Kirov","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Neumann, M., King, D., Beltagy, I., and Ammar, W. (2019, January 1). ScispaCy: Fast and Robust Models for Biomedical Natural Language Processing. Proceedings of the 18th BioNLP Workshop and Shared Task, Florence, Italy.","DOI":"10.18653\/v1\/W19-5034"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nri2532","article-title":"Intravascular immunity: The host-pathogen encounter in blood vessels","volume":"9","author":"Hickey","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fphys.2018.00113","article-title":"Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?","volume":"9","author":"Rosales","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s12964-019-0471-y","article-title":"The regulatory roles of neutrophils in adaptive immunity","volume":"17","author":"Li","year":"2019","journal-title":"Cell Commun.Signal. CCS"},{"key":"ref_48","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. LifeSci. CMLS"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10715","DOI":"10.1007\/s11033-022-07700-x","article-title":"SARS-CoV-2 cell entry beyond the ACE2 receptor","volume":"49","author":"Alipoor","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"del Valle-Mendoza, J., Tarazona-Castro, Y., Merino-Luna, A., Carrillo-Ng, H., Kym, S., Aguilar-Luis, M.A., del Valle, L.J., Aquino-Ortega, R., Martins-Luna, J., and Pe\u00f1a-Tuesta, I. (2022). Comparison of cytokines levels among COVID-19 patients living at sea level and high altitude. BMC Infect. Dis., 22.","DOI":"10.1186\/s12879-022-07079-x"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"St\u00f6whas, A.C., Latshang, T.D., Lo Cascio, C.M., Lautwein, S., Stadelmann, K., Tesler, N., Ayers, L., Berneis, K., Gerber, P.A., and Huber, R. (2013). Effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070081"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Stephens, K.E., Chernyavskiy, P., and Bruns, D.R. (2021). Impact of altitude on COVID-19 infection and death in the United States: A modeling and observational study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0245055"},{"key":"ref_53","first-page":"274","article-title":"Effects of living at higher altitudes on mortality: A narrative review","volume":"5","author":"Burtscher","year":"2014","journal-title":"Aging Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"103443","DOI":"10.1016\/j.resp.2020.103443","article-title":"Does the pathogenesis of SARS-CoV-2 virus decrease at high-altitude?","volume":"277","author":"Dutschmann","year":"2020","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4103\/bjhs.bjhs_7_17","article-title":"Extended longevity at high altitude: Benefits of exposure to chronic hypoxia","volume":"2","year":"2017","journal-title":"BLDE Univ. J. Health Sci."},{"key":"ref_56","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_57","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An inflammatory cytokine signature predicts COVID-19 severity and survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1006\/cyto.1999.0533","article-title":"High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein","volume":"12","author":"Hartmann","year":"2000","journal-title":"Cytokine"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.ccell.2020.10.006","article-title":"COVID-19: Staging of a New Disease","volume":"38","author":"Pujadas","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1056\/NEJMe2009758","article-title":"Asymptomatic Transmission, the Achilles\u2019 Heel of Current Strategies to Control COVID-19","volume":"382","author":"Gandhi","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Huang, Y., Zaas, A.K., Rao, A., Dobigeon, N., Woolf, P.J., Veldman, T., \u00d8ien, N.C., McClain, M.T., Varkey, J.B., and Nicholson, B. (2011). Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002234"},{"key":"ref_62","doi-asserted-by":"crossref","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":"ref_63","doi-asserted-by":"crossref","unstructured":"Sarma, A., Christenson, S.A., Mick, E., DeVoe, C., Deiss, T., Pisco, A.O., Ghale, R., Jauregui, A., Byrne, A., and Moazed, F. (2021). COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone. Res. Sq.","DOI":"10.21203\/rs.3.rs-141578\/v1"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s43630-020-00004-8","article-title":"COVID-19 and the ethnicity link - is there a photochemical link?","volume":"20","author":"Edge","year":"2021","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e140329","DOI":"10.1172\/jci.insight.140329","article-title":"Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections","volume":"5","author":"Remy","year":"2020","journal-title":"JCI Insight"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Mo, Y., Eyre, D.W., Lumley, S.F., Walker, T.M., Shaw, R.H., O\u2019Donnell, D., Butcher, L., Jeffery, K., Donnelly, C.A., and Oxford COVID infection review team (2021). Transmission of community- and hospital-acquired SARS-CoV-2 in hospital settings in the UK: A cohort study. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003816"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13756-021-00988-7","article-title":"Nosocomial infections among COVID-19 patients: An analysis of intensive care unit surveillance data","volume":"10","author":"Ong","year":"2021","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1097\/MCC.0000000000000860","article-title":"Secondary pneumonias in critically ill patients with COVID-19: Risk factors and outcomes","volume":"27","author":"Povoa","year":"2021","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.2147\/IDR.S299774","article-title":"Secondary Infections in Hospitalized COVID-19 Patients: Indian Experience","volume":"14","author":"Vijay","year":"2021","journal-title":"Infect. Drug Resist."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e98960","DOI":"10.1172\/jci.insight.98960","article-title":"Interleukin-7 restores lymphocytes in septic shock: The IRIS-7 randomized clinical trial","volume":"3","author":"Francois","year":"2018","journal-title":"JCI Insight"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.3389\/fimmu.2018.02739","article-title":"Organ-Specific Mechanisms of Transendothelial Neutrophil Migration in the Lung, Liver, Kidney, and Aorta","volume":"9","author":"Maas","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"cm8","DOI":"10.1126\/stke.4072007cm8","article-title":"Hypoxia-inducible factor 1 (HIF-1) pathway","volume":"2007","author":"Semenza","year":"2007","journal-title":"Sci. STKE"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/00024382-200204000-00005","article-title":"Acute hypoxemia in humans enhances the neutrophil inflammatory response","volume":"17","author":"Tamura","year":"2002","journal-title":"Shock"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"11475","DOI":"10.1038\/s41598-018-29659-1","article-title":"Hypoxia increases neutrophil-driven matrix destruction after exposure to Mycobacterium tuberculosis","volume":"8","author":"Ong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Lodge, K.M., Cowburn, A.S., Li, W., and Condliffe, A.M. (2020). The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041183"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"541","DOI":"10.3389\/fimmu.2017.00541","article-title":"Hypoxia Modulates the Response of Mast Cells to Staphylococcus aureus Infection","volume":"8","author":"Brogden","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/BF03401959","article-title":"The regulation of interleukin-8 by hypoxia in human macrophages\u2014A potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS)","volume":"7","author":"Hirani","year":"2001","journal-title":"Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eaal2861","DOI":"10.1126\/sciimmunol.aal2861","article-title":"Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism","volume":"2","author":"Thompson","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2894","DOI":"10.1161\/01.CIR.0000042674.89762.20","article-title":"Neutrophil infiltration of culprit lesions in acute coronary syndromes","volume":"106","author":"Naruko","year":"2002","journal-title":"Circulation"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","article-title":"Clinical Characteristics of Coronavirus Disease 2019 in China","volume":"382","author":"Guan","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_81","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":"Netea","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"Qin","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1182\/bloodadvances.2020003568","article-title":"A neutrophil activation signature predicts critical illness and mortality in COVID-19","volume":"5","author":"Meizlish","year":"2021","journal-title":"Blood Adv."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s41587-020-0602-4","article-title":"COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis","volume":"38","author":"Chua","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13073-020-00823-5","article-title":"Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients","volume":"13","author":"Aschenbrenner","year":"2021","journal-title":"Genome Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1182\/blood.2020007008","article-title":"Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome","volume":"136","author":"Middleton","year":"2020","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"eabo2202","DOI":"10.1126\/sciimmunol.abo2202","article-title":"Divergent SARS-CoV-2 Omicron&#x2013;reactive T and B cell responses in COVID-19 vaccine recipients","volume":"7","author":"GeurtsvanKessel","year":"2022","journal-title":"Sci. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:56:09Z","timestamp":1760147769000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/1\/104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,30]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["v15010104"],"URL":"https:\/\/doi.org\/10.3390\/v15010104","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,30]]}}}