{"doi":"10.1101/2021.02.09.430269","title":"Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19","abstract":"Abstract The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUC training = 0.799, p-value = 4.2e-6; multi-class AUC validation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression. Summary Feyaerts et al. demonstrate that an integrated analysis of plasma and single-cell proteomics differentiates COVID-19 severity and reveals severity-specific biological signatures associated with the dysregulation of the JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks and the mobilization of the renin-angiotensin and hemostasis systems.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213829,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8036,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271982,"name":"Julien Hédou","orcid":"0000-0003-4721-4797","position":1,"is_corresponding":false},{"id":806422,"name":"Joshua Gillard","orcid":"0000-0001-8509-2212","position":2,"is_corresponding":false},{"id":238075,"name":"Han Chen","orcid":"0000-0002-1722-8736","position":3,"is_corresponding":false},{"id":278124,"name":"Eileen S. Tsai","orcid":"0000-0001-6714-1439","position":4,"is_corresponding":false},{"id":294166,"name":"Laura S. Peterson","orcid":"0000-0002-4830-5271","position":5,"is_corresponding":false},{"id":278126,"name":"Kazuo Ando","orcid":"0000-0003-1778-1344","position":6,"is_corresponding":false},{"id":226833,"name":"Monali Manohar","orcid":"0000-0002-1869-2645","position":7,"is_corresponding":false},{"id":617332,"name":"Evan Do","orcid":null,"position":8,"is_corresponding":false},{"id":466152,"name":"Gopal Krishna Dhondalay","orcid":"0000-0002-1020-0175","position":9,"is_corresponding":false},{"id":391192,"name":"Jessica Fitzpatrick","orcid":"0000-0002-2686-7628","position":10,"is_corresponding":false},{"id":616082,"name":"Maja Artandi","orcid":"0000-0003-2342-6277","position":11,"is_corresponding":false},{"id":616084,"name":"Iris Chang","orcid":"0009-0007-1971-8513","position":12,"is_corresponding":false},{"id":631335,"name":"Theo T. Snow","orcid":null,"position":13,"is_corresponding":false},{"id":344289,"name":"R. Sharon Chinthrajah","orcid":"0000-0003-2467-4256","position":14,"is_corresponding":false},{"id":241990,"name":"Christopher Warren","orcid":"0000-0002-8924-3329","position":15,"is_corresponding":false},{"id":804666,"name":"Rich Wittman","orcid":null,"position":16,"is_corresponding":false},{"id":642233,"name":"Justin Meyerowitz","orcid":"0000-0001-7194-8286","position":17,"is_corresponding":false},{"id":278121,"name":"Edward A. Ganio","orcid":"0000-0002-1088-0377","position":18,"is_corresponding":false},{"id":278113,"name":"Ina A. Stelzer","orcid":"0000-0002-9974-4661","position":19,"is_corresponding":false},{"id":278125,"name":"Xiaoyuan Han","orcid":"0000-0001-6394-3055","position":20,"is_corresponding":false},{"id":464286,"name":"Franck Verdonk","orcid":"0000-0001-7061-5594","position":21,"is_corresponding":false},{"id":278123,"name":"Dyani Gaudillière","orcid":"0000-0003-3017-5939","position":22,"is_corresponding":false},{"id":328724,"name":"Nilanjan Mukherjee","orcid":"0000-0001-5290-9185","position":23,"is_corresponding":false},{"id":278122,"name":"Amy S. Tsai","orcid":"0000-0002-2380-6424","position":24,"is_corresponding":false},{"id":464287,"name":"Kristen K. Rumer","orcid":"0000-0003-2713-8811","position":25,"is_corresponding":false},{"id":55231,"name":"Sizun Jiang","orcid":"0000-0001-6149-3142","position":26,"is_corresponding":false},{"id":744455,"name":"Sergio Iván Valdés‐Ferrer","orcid":"0000-0002-4863-6484","position":27,"is_corresponding":false},{"id":252180,"name":"J. Daniel Kelly","orcid":"0000-0002-7616-0321","position":28,"is_corresponding":false},{"id":3338,"name":"David Furman","orcid":"0000-0002-3654-9519","position":29,"is_corresponding":false},{"id":226949,"name":"Nima Aghaeepour","orcid":"0000-0002-6117-8764","position":30,"is_corresponding":false},{"id":34078,"name":"Martin S. Angst","orcid":"0000-0002-1550-8136","position":31,"is_corresponding":false},{"id":226844,"name":"Scott D. Boyd","orcid":"0000-0003-0963-044X","position":32,"is_corresponding":false},{"id":226843,"name":"Benjamin A. Pinsky","orcid":"0000-0001-8751-4810","position":33,"is_corresponding":false},{"id":35731,"name":"Garry P. Nolan","orcid":"0000-0002-8862-9043","position":34,"is_corresponding":false},{"id":36438,"name":"Kari C. Nadeau","orcid":"0000-0002-2146-2955","position":35,"is_corresponding":false},{"id":86469,"name":"Brice Gaudillière","orcid":"0000-0002-3475-5706","position":36,"is_corresponding":false},{"id":107287,"name":"David R. McIlwain","orcid":"0000-0002-2537-0273","position":37,"is_corresponding":false},{"id":628496,"name":"Dorien Feyaerts","orcid":"0000-0002-0795-6625","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:41.672172Z","pmid":"33594362","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}