Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

Hadjadj, Jerome; Yatim, Nader; Barnabei, Laura; Corneau, Aurelien; Boussier, Jeremy; Pere, Helene; Charbit, Bruno; Bondet, Vincent; Chenevier-Gobeaux, Camille; Breillat, Paul; Carlier, Nicolas; Gauzit, Remy; Morbieu, Caroline; Pene, Frederic; Marin, Nathalie; Roche, Nicolas; Szwebel, Tali-Anne; Smith, Nikaia; Merkling, Sarah; Treluyer, Jean-Marc; Veyer, David; Mouthon, Luc; Blanc, Catherine; Tharaux, Pierre-Louis; Rozenberg, Flore; Fischer, Alain; Duffy, Darragh; Rieux-Laucat, Frederic; Kerneis, Solen; Terrier, Benjamin

Background: Coronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known. Methods: We performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy. Results: A unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFκB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines. Conclusion: We propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.