Longitudinal Single Cell Atlas Identifies Type I Interferon Response as an Early Transient Prognostic Signature of COVID-19 Severity

The clinical spectrum of COVID-19 ranges from asymptomatic or mildly symptomatic illness to pneumonia, critical illness and death. Molecular markers early in the disease course (Days 1-8) that identify patients at high risk for progression are scarce, due to the paucity of relevant longitudinal studies. We performed longitudinal single cell RNA-seq on 286 peripheral blood samples from 108 age- and gender-matched COVID-19 patients, 73 of which had at least one early sample. By examining discrete cell subtypes as well as continuous single cell states, we identified upregulation of genes related to type I interferon (IFN) signaling as the predominant cellular prognostic signature of future disease severity. Type I IFN signaling was dynamic and complex, spiking early in Progressors and then receding to the level of Non-Progressors at the very next sampling. Across the entire cohort, expression of type I IFN signaling genes dropped steadily, falling to asymptomatic levels by Day 14 regardless of severity. Moreover, in severe and critical cases, IFN signaling was deficient during Days 5-8, potentially due to upregulation of <em>SOCS3</em> and other negative regulators. In summary, we have identified an early expression signature that may predict COVID-19 severity, as well as potential mechanisms underlying the dysfunctional host immune response in severe disease.