Time-resolved Systems Immunology Reveals a Late Juncture Linked to Fatal COVID-19

Liu, Can; Martins, Andrew J.; Lau, William W.; Rachmaninoff, Nicholas; Chen, Jinguo; Imberti, Luisa; Mostaghimi, Darius; Fink, Danielle L.; Burbelo, Peter D.; Dobbs, Kerry; Delmonte, Ottavia M.; Bansal, Neha; Failla, Laura; Sottini, Alessandra; Quiros-Roldan, Eugenia; Lee Han, Kyu; Sellers, Brian A.; Cheung, Foo; Sparks, Rachel; Chun, Tae-Wook; Moir, Susan; Lionakis, Michail S.; Rossi, Camillo; Su, Helen C.; Kuhns, Douglas B.; Cohen, Jeffrey I.; Notarangelo, Luigi D.; Tsang, John S.; Abers, Michael S.; Apps, Richard; Bosticardo, Marita; Milanez-Almeida, Pedro; Mulè, Matthew P.; Shaw, Elana; Zhang, Yu; Castelli, Francesco; Muiesan, Maria Lorenza; Tomasoni, Gabriele; Scolari, Francesco; Tucci, Alessandra

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 CD56dimCD16hi NK cells linked positively to circulating IL-15. CD8+ T cell activation was apparent without signs of exhaustion. While 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-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.