{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:17:37Z","timestamp":1772173057834,"version":"3.50.1"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"australian research council discovery project grant","award":["DP170100654"],"award-info":[{"award-number":["DP170100654"]}]},{"DOI":"10.13039\/501100007156","name":"innovation and technology commission - hong kong","doi-asserted-by":"publisher","award":["AIR@innoHK programme"],"award-info":[{"award-number":["AIR@innoHK programme"]}],"id":[{"id":"10.13039\/501100007156","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Training Program Tuition Fee Offset and Stipend Scholarship"},{"name":"Chen Family Research Scholarship"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>COVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or dysfunctional immune responses to the virus, is critical to effectively treat these patients. Currently, our understanding of cell-cell interactions across different disease states, and how such interactions may drive pathogenic outcomes, is incomplete. Here, we developed a generalizable and scalable workflow for identifying cells that are differentially interacting across COVID-19 patients with distinct disease outcomes and use this to examine eight public single-cell RNA-seq datasets (six from peripheral blood mononuclear cells, one from bronchoalveolar lavage and one from nasopharyngeal), with a total of 211 individual samples. By characterizing the cell-cell interaction patterns across epithelial and immune cells in lung tissues for patients with varying disease severity, we illustrate diverse communication patterns across individuals, and discover heterogeneous communication patterns among moderate and severe patients. We further illustrate patterns derived from cell-cell interactions are potential signatures for discriminating between moderate and severe patients. Overall, this workflow can be generalized and scaled to combine multiple scRNA-seq datasets to uncover cell-cell interactions.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010495","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T13:39:03Z","timestamp":1664977143000},"page":"e1010495","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Scalable workflow for characterization of cell-cell communication in COVID-19 patients"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4299-7326","authenticated-orcid":true,"given":"Yingxin","family":"Lin","sequence":"first","affiliation":[]},{"given":"Lipin","family":"Loo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5815-2400","authenticated-orcid":true,"given":"Andy","family":"Tran","sequence":"additional","affiliation":[]},{"given":"David M.","family":"Lin","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0876-0341","authenticated-orcid":true,"given":"Cesar","family":"Moreno","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Hesselson","sequence":"additional","affiliation":[]},{"given":"G. Gregory","family":"Neely","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5271-2603","authenticated-orcid":true,"given":"Jean Y. H.","family":"Yang","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"pcbi.1010495.ref001","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/s41592-021-01223-2","article-title":"Publisher Correction: The triumphs and limitations of computational methods for scRNA-seq.","volume":"18","author":"PV Kharchenko","year":"2021","journal-title":"Nat Methods."},{"key":"pcbi.1010495.ref002","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41592-019-0654-x","article-title":"Orchestrating single-cell analysis with Bioconductor.","volume":"17","author":"RA Amezquita","year":"2020","journal-title":"Nat Methods"},{"key":"pcbi.1010495.ref003","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13578-019-0314-y","article-title":"The single-cell sequencing: new developments and medical applications","volume":"9","author":"X Tang","year":"2019","journal-title":"Cell Biosci"},{"key":"pcbi.1010495.ref004","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/s12276-020-0422-0","article-title":"Single-cell transcriptomics in cancer: computational challenges and opportunities","volume":"52","author":"J Fan","year":"2020","journal-title":"Exp Mol Med"},{"key":"pcbi.1010495.ref005","doi-asserted-by":"crossref","first-page":"eaan4730","DOI":"10.1126\/scitranslmed.aan4730","article-title":"Single-cell analyses to tailor treatments.","volume":"9","author":"AK Shalek","year":"2017","journal-title":"Sci Transl Med."},{"key":"pcbi.1010495.ref006","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell-cell interactions and communication from gene expression","volume":"22","author":"E Armingol","year":"2021","journal-title":"Nat Rev Genet"},{"key":"pcbi.1010495.ref007","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat.","volume":"12","author":"S Jin","year":"2021","journal-title":"Nat Commun."},{"key":"pcbi.1010495.ref008","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.celrep.2018.10.047","article-title":"Analysis of single-cell RNA-seq identifies cell-cell communication associated with tumor characteristics","volume":"25","author":"MP Kumar","year":"2018","journal-title":"Cell Rep"},{"key":"pcbi.1010495.ref009","doi-asserted-by":"crossref","first-page":"105730","DOI":"10.1016\/j.envint.2020.105730","article-title":"Airborne transmission of SARS-CoV-2: The world should face the reality.","volume":"139","author":"L Morawska","year":"2020","journal-title":"Environ Int"},{"key":"pcbi.1010495.ref010","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41586-020-2157-4","article-title":"Construction of a human cell landscape at single-cell level","volume":"581","author":"X Han","year":"2020","journal-title":"Nature"},{"key":"pcbi.1010495.ref011","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1164\/rccm.201712-2410OC","article-title":"Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis","volume":"199","author":"PA Reyfman","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"pcbi.1010495.ref012","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/s41591-019-0468-5","article-title":"A cellular census of human lungs identifies novel cell states in health and in asthma","volume":"25","author":"FA Vieira Braga","year":"2019","journal-title":"Nat Med"},{"key":"pcbi.1010495.ref013","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ijid.2020.03.020","article-title":"Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19).","volume":"94","author":"H Nishiura","year":"2020","journal-title":"Int J Infect Dis"},{"key":"pcbi.1010495.ref014","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study","volume":"8","author":"X Yang","year":"2020","journal-title":"Lancet Respir Med"},{"key":"pcbi.1010495.ref015","article-title":"SARS-CoV-2 viral load is associated with increased disease severity and mortality.","author":"J Fajnzylber","year":"2020","journal-title":"Research Square. Research Square"},{"key":"pcbi.1010495.ref016","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.jaci.2020.09.010","article-title":"Coronavirus disease 2019 in patients with inborn errors of immunity: An international study","volume":"147","author":"I Meyts","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"pcbi.1010495.ref017","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":"C Qin","year":"2020","journal-title":"Clin Infect Dis"},{"key":"pcbi.1010495.ref018","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.chom.2016.01.007","article-title":"Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice.","volume":"19","author":"R Channappanavar","year":"2016","journal-title":"Cell Host Microbe"},{"key":"pcbi.1010495.ref019","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":"RL Chua","year":"2020","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010495.ref020","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":"M Liao","year":"2020","journal-title":"Nat Med"},{"key":"pcbi.1010495.ref021","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-020-0944-y","article-title":"A single-cell atlas of the peripheral immune response in patients with severe COVID-19","volume":"26","author":"AJ Wilk","year":"2020","journal-title":"Nat Med"},{"key":"pcbi.1010495.ref022","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/s41590-020-0762-x","article-title":"Single-cell landscape of immunological responses in patients with COVID-19","volume":"21","author":"J-Y Zhang","year":"2020","journal-title":"Nat Immunol"},{"key":"pcbi.1010495.ref023","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1126\/science.abc6261","article-title":"Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans","volume":"369","author":"PS Arunachalam","year":"2020","journal-title":"Science"},{"key":"pcbi.1010495.ref024","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"},{"key":"pcbi.1010495.ref025","doi-asserted-by":"crossref","first-page":"eabd1554","DOI":"10.1126\/sciimmunol.abd1554","article-title":"Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19.","volume":"5","author":"JS Lee","year":"2020","journal-title":"Sci Immunol."},{"key":"pcbi.1010495.ref026","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.immuni.2020.07.009","article-title":"Single-cell sequencing of peripheral mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients","volume":"53","author":"L Zhu","year":"2020","journal-title":"Immunity"},{"key":"pcbi.1010495.ref027","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cell.2020.05.032","article-title":"Proteomic and metabolomic characterization of COVID-19 patient Sera","volume":"182","author":"B Shen","year":"2020","journal-title":"Cell"},{"key":"pcbi.1010495.ref028","doi-asserted-by":"crossref","first-page":"e9389","DOI":"10.15252\/msb.20199389","article-title":"scClassify: sample size estimation and multiscale classification of cells using single and multiple reference","volume":"16","author":"Y Lin","year":"2020","journal-title":"Mol Syst Biol"},{"key":"pcbi.1010495.ref029","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1128\/CMR.00012-11","article-title":"The airway epithelium: Soldier in the fight against respiratory viruses","volume":"24","author":"M Vareille","year":"2011","journal-title":"Clin Microbiol Rev"},{"key":"pcbi.1010495.ref030","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/mi.2015.126","article-title":"Control of local immunity by airway epithelial cells","volume":"9","author":"M Weitnauer","year":"2016","journal-title":"Mucosal Immunol"},{"key":"pcbi.1010495.ref031","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41577-020-00470-2","article-title":"Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19","volume":"21","author":"R Alon","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"pcbi.1010495.ref032","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes.","volume":"15","author":"M Efremova","year":"2020","journal-title":"Nat Protoc"},{"key":"pcbi.1010495.ref033","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.1093\/nar\/gkaa183","article-title":"SingleCellSignalR: inference of intercellular networks from single-cell transcriptomics","volume":"48","author":"S Cabello-Aguilar","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010495.ref034","doi-asserted-by":"crossref","first-page":"e1006378","DOI":"10.1371\/journal.pcbi.1006378","article-title":"clusterExperiment and RSEC: A Bioconductor package and framework for clustering of single-cell and other large gene expression datasets","volume":"14","author":"D Risso","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010495.ref035","first-page":"2019","article-title":"A single-cell atlas of the human healthy airways.","author":"M Deprez","year":"2019","journal-title":"Cold Spring Harbor Laboratory."},{"key":"pcbi.1010495.ref036","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","article-title":"A molecular cell atlas of the human lung from single-cell RNA sequencing","volume":"587","author":"KJ Travaglini","year":"2020","journal-title":"Nature"},{"key":"pcbi.1010495.ref037","doi-asserted-by":"crossref","first-page":"9775","DOI":"10.1073\/pnas.1820006116","article-title":"scMerge leverages factor analysis, stable expression, and pseudoreplication to merge multiple single-cell RNA-seq datasets","volume":"116","author":"Y Lin","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1010495.ref038","first-page":"363","article-title":"The trinity of COVID-19: immunity, inflammation and intervention","author":"MZ Tay","year":"2020","journal-title":"Nature Reviews Immunology"},{"key":"pcbi.1010495.ref039","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41577-020-0320-7","article-title":"Complement as a target in COVID-19?","volume":"20","author":"AM Risitano","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"pcbi.1010495.ref040","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41577-020-0321-6","article-title":"The potential danger of suboptimal antibody responses in COVID-19","volume":"20","author":"A Iwasaki","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"pcbi.1010495.ref041","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"W Sungnak","year":"2020","journal-title":"Nat Med"},{"key":"pcbi.1010495.ref042","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nri2470","article-title":"Annexin A1 and glucocorticoids as effectors of the resolution of inflammation","volume":"9","author":"M Perretti","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"pcbi.1010495.ref043","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1056\/NEJMra050541","article-title":"Antiinflammatory action of glucocorticoids\u2014new mechanisms for old drugs","volume":"353","author":"T Rhen","year":"2005","journal-title":"N Engl J Med"},{"key":"pcbi.1010495.ref044","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: modeling intercellular communication by linking ligands to target genes.","volume":"17","author":"R Browaeys","year":"2020","journal-title":"Nat Methods"},{"key":"pcbi.1010495.ref045","doi-asserted-by":"crossref","first-page":"5011","DOI":"10.1038\/s41467-020-18873-z","article-title":"Predicting cell-to-cell communication networks using NATMI.","volume":"11","author":"R Hou","year":"2020","journal-title":"Nat Commun."},{"key":"pcbi.1010495.ref046","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41587-020-0442-2","article-title":"Dissecting cellular crosstalk by sequencing physically interacting cells","volume":"38","author":"A Giladi","year":"2020","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010495.ref047","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1186\/s13059-019-1861-6","article-title":"Feature selection and dimension reduction for single-cell RNA-Seq based on a multinomial model","volume":"20","author":"FW Townes","year":"2019","journal-title":"Genome Biol"},{"key":"pcbi.1010495.ref048","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters","author":"G Yu","year":"2012","journal-title":"OMICS: A Journal of Integrative Biology"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010495","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T08:47:16Z","timestamp":1701161236000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010495"}},"subtitle":[],"editor":[{"given":"Curtis","family":"Huttenhower","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,10,5]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010495","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.12.30.424641","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,5]]}}}