tetano
Editor, Senior Moderator
J Clin Invest
. 2024 May 1;134(9):e176640.
doi: 10.1172/JCI176640. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality
Jeremy P Gygi[SUP] 1 [/SUP], Cole Maguire[SUP] 2 [/SUP], Ravi K Patel[SUP] 3 [/SUP], Pramod Shinde[SUP] 4 [/SUP], Anna Konstorum[SUP] 1 [/SUP], Casey P Shannon[SUP] 5 6 [/SUP], Leqi Xu[SUP] 7 [/SUP], Annmarie Hoch[SUP] 8 9 [/SUP], Naresh Doni Jayavelu[SUP] 10 [/SUP], Elias K Haddad[SUP] 11 [/SUP]; IMPACC Network; Elaine F Reed[SUP] 12 [/SUP], Monica Kraft[SUP] 13 [/SUP], Grace A McComsey[SUP] 14 [/SUP], Jordan P Metcalf[SUP] 15 [/SUP], Al Ozonoff[SUP] 8 9 16 17 [/SUP], Denise Esserman[SUP] 7 [/SUP], Charles B Cairns[SUP] 11 [/SUP], Nadine Rouphael[SUP] 18 [/SUP], Steven E Bosinger[SUP] 18 [/SUP], Seunghee Kim-Schulze[SUP] 13 [/SUP], Florian Krammer[SUP] 13 19 [/SUP], Lindsey B Rosen[SUP] 20 [/SUP], Harm van Bakel[SUP] 13 [/SUP], Michael Wilson[SUP] 3 [/SUP], Walter L Eckalbar[SUP] 3 [/SUP], Holden T Maecker[SUP] 21 [/SUP], Charles R Langelier[SUP] 3 [/SUP], Hanno Steen[SUP] 9 22 [/SUP], Matthew C Altman[SUP] 10 [/SUP], Ruth R Montgomery[SUP] 1 [/SUP], Ofer Levy[SUP] 9 16 17 [/SUP], Esther Melamed[SUP] 2 [/SUP], Bali Pulendran[SUP] 21 [/SUP], Joann Diray-Arce[SUP] 8 9 17 [/SUP], Kinga K Smolen[SUP] 9 17 [/SUP], Gabriela K Fragiadakis[SUP] 3 [/SUP], Patrice M Becker[SUP] 20 [/SUP], Rafick P Sekaly[SUP] 14 [/SUP], Lauren Ir Ehrlich[SUP] 2 [/SUP], Slim Fourati[SUP] 14 [/SUP], Bjoern Peters[SUP] 4 23 [/SUP], Steven H Kleinstein[SUP] 1 [/SUP], Leying Guan[SUP] 7 [/SUP]
Affiliations
BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
Keywords: Adaptive immunity; COVID-19; Immunology; Innate immunity.
. 2024 May 1;134(9):e176640.
doi: 10.1172/JCI176640. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality
Jeremy P Gygi[SUP] 1 [/SUP], Cole Maguire[SUP] 2 [/SUP], Ravi K Patel[SUP] 3 [/SUP], Pramod Shinde[SUP] 4 [/SUP], Anna Konstorum[SUP] 1 [/SUP], Casey P Shannon[SUP] 5 6 [/SUP], Leqi Xu[SUP] 7 [/SUP], Annmarie Hoch[SUP] 8 9 [/SUP], Naresh Doni Jayavelu[SUP] 10 [/SUP], Elias K Haddad[SUP] 11 [/SUP]; IMPACC Network; Elaine F Reed[SUP] 12 [/SUP], Monica Kraft[SUP] 13 [/SUP], Grace A McComsey[SUP] 14 [/SUP], Jordan P Metcalf[SUP] 15 [/SUP], Al Ozonoff[SUP] 8 9 16 17 [/SUP], Denise Esserman[SUP] 7 [/SUP], Charles B Cairns[SUP] 11 [/SUP], Nadine Rouphael[SUP] 18 [/SUP], Steven E Bosinger[SUP] 18 [/SUP], Seunghee Kim-Schulze[SUP] 13 [/SUP], Florian Krammer[SUP] 13 19 [/SUP], Lindsey B Rosen[SUP] 20 [/SUP], Harm van Bakel[SUP] 13 [/SUP], Michael Wilson[SUP] 3 [/SUP], Walter L Eckalbar[SUP] 3 [/SUP], Holden T Maecker[SUP] 21 [/SUP], Charles R Langelier[SUP] 3 [/SUP], Hanno Steen[SUP] 9 22 [/SUP], Matthew C Altman[SUP] 10 [/SUP], Ruth R Montgomery[SUP] 1 [/SUP], Ofer Levy[SUP] 9 16 17 [/SUP], Esther Melamed[SUP] 2 [/SUP], Bali Pulendran[SUP] 21 [/SUP], Joann Diray-Arce[SUP] 8 9 17 [/SUP], Kinga K Smolen[SUP] 9 17 [/SUP], Gabriela K Fragiadakis[SUP] 3 [/SUP], Patrice M Becker[SUP] 20 [/SUP], Rafick P Sekaly[SUP] 14 [/SUP], Lauren Ir Ehrlich[SUP] 2 [/SUP], Slim Fourati[SUP] 14 [/SUP], Bjoern Peters[SUP] 4 23 [/SUP], Steven H Kleinstein[SUP] 1 [/SUP], Leying Guan[SUP] 7 [/SUP]
Affiliations
- PMID: 38690733
- DOI: 10.1172/JCI176640
BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
Keywords: Adaptive immunity; COVID-19; Immunology; Innate immunity.