Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison

Abstract

Abstract A central paradigm of immunity is that interferon (IFN) mediated antiviral responses precede the pro-inflammatory ones, optimizing host protection and minimizing collateral damage 1,2 . Here, we report that for COVID-19 this does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 COVID-19 patients hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production is both diminished and delayed, induced only in a fraction of patients as they become critically ill. On the contrary, pro-inflammatory cytokines such as TNF, IL-6 and IL-8 are produced before IFNs, in all patients, and persist for a prolonged time. By comparison, in 16 flu patients hospitalized for pneumonia with similar clinicopathological characteristics to COVID-19 and 24 milder non-hospitalized flu patients IFN-λ and type I IFN are robustly induced, earlier, at higher levels and independently of disease severity, while pro-inflammatory cytokines are only acutely and transiently produced. Notably, higher IFN-λ levels in COVID-19 patients correlate with lower viral load in bronchial aspirates and faster viral clearance, and a higher IFN-λ:type I IFN ratio with improved outcome of critically ill patients. Moreover, altered cytokine patterns in COVID-19 patients correlate with longer hospitalization time and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19 contributing to persistent viral presence, hyperinflammation and respiratory failure.