{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:25:09Z","timestamp":1785450309829,"version":"3.56.0"},"reference-count":69,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AMED","award":["JP22ama121019"],"award-info":[{"award-number":["JP22ama121019"]}]},{"name":"New Energy and Industrial Technology Development Organization","award":["JP22ama121019"],"award-info":[{"award-number":["JP22ama121019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild\/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell\u2013cell communication analysis revealed representative ligand\u2013receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.<\/jats:p>","DOI":"10.3390\/ijms25073841","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T13:42:30Z","timestamp":1711892550000},"page":"3841","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19"],"prefix":"10.3390","volume":"25","author":[{"given":"Lin","family":"Zhang","sequence":"first","affiliation":[{"name":"Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Miyagi, Japan"},{"name":"Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai 980-8579, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafumi","family":"Nishi","sequence":"additional","affiliation":[{"name":"Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Miyagi, Japan"},{"name":"Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai 980-8579, Miyagi, Japan"},{"name":"Faculty of Core Research, Ochanomizu University, Tokyo 112-8610, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Miyagi, Japan"},{"name":"Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai 980-8579, Miyagi, Japan"},{"name":"Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Miyagi, Japan"},{"name":"Department of In Silico Analyses, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20201129","DOI":"10.1084\/jem.20201129","article-title":"SARS-CoV-2\u2013Triggered Neutrophil Extracellular Traps Mediate COVID-19 Pathology","volume":"217","author":"Veras","year":"2020","journal-title":"J. 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