Bifurcated monocyte states are predictive of mortality in severe COVID-19.
| العنوان: | Bifurcated monocyte states are predictive of mortality in severe COVID-19. |
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| المؤلفون: | Cillo AR; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Somasundaram A; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Shan F; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Integrative Systems Biology (ISB) Graduate Program, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA., Cardello C; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Workman CJ; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Kitsios GD; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Ruffin A; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Graduate Program of Microbiology and Immunology (PMI), University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA., Kunning S; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Lampenfeld C; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Onkar S; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Graduate Program of Microbiology and Immunology (PMI), University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA., Grebinoski S; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Graduate Program of Microbiology and Immunology (PMI), University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, USA., Deshmukh G; Meso Scale Discovery, A division of Meso Scale Diagnostics, LLC, 1601 Research Boulevard, Rockville, MD 20850-3173, USA., Methe B; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Liu C; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Nambulli S; Center for Vaccine Research, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Andrews L; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA., Duprex WP; Center for Vaccine Research, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Joglekar AV; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Center for Systems Immunology, Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Benos PV; Department of Computer Science, University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, PA 15260, USA.; Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Avenue, Pittsburgh, PA 15213, USA., Ray P; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; University of Pittsburgh Asthma Institute at the University of Pittsburgh Medical Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA., Ray A; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; University of Pittsburgh Asthma Institute at the University of Pittsburgh Medical Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA., McVerry BJ; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Zhang Y; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Lee JS; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA.; Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Das J; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Center for Systems Immunology, Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Singh H; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Center for Systems Immunology, Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Morris A; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15213, USA., Bruno TC; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA., Vignali DAA; Department of Immunology, School of Medicine, University of Pittsburgh. Pittsburgh, PA 15260, USA.; Tumor Microenvironment Center, UPMC Hillman Cancer Center. Pittsburgh, PA 15232, USA.; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2021 Feb 10. Date of Electronic Publication: 2021 Feb 10. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations 1 , ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality 2,3 . Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics. Competing Interests: Conflicts of Interest DAAV: cofounder and stockholder – Novasenta, Tizona and Potenza; stock holder – Tizona, Oncorus and Werewolf; patents licensed and royalties - Astellas, BMS; scientific advisory board member - Tizona, Werewolf, F-Star, Bicara; consultant - Astellas, BMS, Almirall, Incyte; research funding – BMS, Astellas and Novasenta. G.D.K.: research funding – Karius, Inc. T.C.B: research funding – Alkermes and Pfizer. Remaining authors declare no competing interests. |
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| معلومات مُعتمدة: | P01 AI108545 United States AI NIAID NIH HHS; P01 HL103455 United States HL NHLBI NIH HHS |
| تواريخ الأحداث: | Date Created: 20210217 Latest Revision: 20240216 |
| رمز التحديث: | 20240216 |
| مُعرف محوري في PubMed: | PMC7885916 |
| DOI: | 10.1101/2021.02.10.430499 |
| PMID: | 33594364 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2021.02.10.430499 |
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