Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19.
Can Liu, Andrew J Martins, William W Lau, Nicholas Rachmaninoff, Jinguo Chen, Luisa Imberti, Darius Mostaghimi, Danielle L Fink, Peter D Burbelo, Kerry Dobbs, Ottavia M Delmonte, Neha Bansal, Laura Failla, Alessandra Sottini, Eugenia Quiros-Roldan, Kyu Lee Han, Brian A Sellers, Foo Cheung, Rachel Sparks, Tae-Wook Chun, Susan Moir, Michail S Lionakis, NIAID COVID Consortium, COVID Clinicians, Camillo Rossi, Helen C Su, Douglas B Kuhns, Jeffrey I Cohen, Luigi D Notarangelo, John S Tsang
Author Information
Can Liu: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; Graduate Program in Biological Sciences, University of Maryland, College Park, MD 20742, USA.
Andrew J Martins: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
William W Lau: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; Office of Intramural Research, CIT, NIH, Bethesda, MD 20892, USA.
Nicholas Rachmaninoff: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; Graduate Program in Biological Sciences, University of Maryland, College Park, MD 20742, USA.
Jinguo Chen: NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
Darius Mostaghimi: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
Danielle L Fink: Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 20701, USA.
Peter D Burbelo: National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
Kerry Dobbs: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
Ottavia M Delmonte: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
Neha Bansal: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
Laura Failla: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
Eugenia Quiros-Roldan: Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili di Brescia, Brescia 25123, Italy.
Kyu Lee Han: NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
Brian A Sellers: NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
Foo Cheung: NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
Rachel Sparks: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA.
Tae-Wook Chun: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Susan Moir: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA.
Michail S Lionakis: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
Camillo Rossi: ASST Spedali Civili di Brescia, Brescia 25123, Italy.
Helen C Su: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
Douglas B Kuhns: Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 20701, USA.
Jeffrey I Cohen: Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA.
Luigi D Notarangelo: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
John S Tsang: Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA; NIH Center for Human Immunology, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: john.tsang@nih.gov.
COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56CD16 NK cells linked positively to circulating interleukin (IL)-15. CD8 T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.
