Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity irrespective of virus

Abstract

SARS-CoV-2 pandemic, the fourth pandemic of the decade, has underscored gaps in global pandemic preparedness and the need for generalizable tests to avert overwhelming healthcare systems worldwide, irrespective of a virus. We integrated 4,780 blood transcriptome profiles from patients infected with one of 16 viruses across 34 independent cohorts from 18 countries, and 71 scRNA-seq profiles of 264,224 immune cells across three independent cohorts. We found a myeloid cell-dominated conserved host response associated with severity. It showed increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells with increased severity. We identified four gene modules that delineate distinct trajectories associated with mild and severe outcomes, and show the interferon response was decoupled from protective host response during severe viral infection. These modules distinguished non-severe from severe viral infection with clinically useful accuracy. Together, our findings provide insights into immune response dynamics during viral infection, and identify factors that may influence patient outcomes.

COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone

“…2e – f , Supplementary Data 11 ), suggesting that a dysregulated interferon response in the lower respiratory tract may characterize severe COVID-19. This hypothesis is supported by recent findings of impaired interferon signaling in peripheral blood immune cells of patients with severe versus mild COVID-19 19 , and a recent report suggesting that a dysregulated interferon response may be a universal characteristic of severe viral infections 20 .…”

COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and may be modified by dexamethasone

“…The copyright holder for this preprint this version posted January 4, 2021. ; https://doi.org/10.1101/2020.12.28.20248552 doi: medRxiv preprint patients with severe disease, we observed decoupling of this relationship for several ISGs (Figures 2e-f, Supplementary Data 11), suggesting that a dysregulated interferon response in the lower respiratory tract may characterize severe COVID-19. This hypothesis is supported by recent findings of impaired interferon signaling in peripheral blood immune cells of patients with severe versus mild COVID-19 17 , and a recent report suggesting that a dysregulated interferon response may be a universal characteristic of severe viral infections 18 .…”

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

“…For example, in an integrated multicohort analysis of viral disease severity, Zheng, et al report a gene module that includes several markers of immature neutrophils (eg. CEACAM8, DEFA4, LCN2) that is enriched in other viral infections including influenza and RSV (105). Additionally, a six-mRNA classifier of viral disease severity, which includes DEFA4, trained on non-COVID-19 viral infections was found to also predict COVID-19 severity (106).…”