Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

Kreutmair, Stefanie; Unger, Susanne; Núñez, Nicolás Gonzalo; Ingelfinger, Florian; Alberti, Chiara; De Feo, Donatella; Krishnarajah, Sinduya; Kauffmann, Manuel; Friebel, Ekaterina; Babaei, Sepideh; Gaborit, Benjamin; Lutz, Mirjam; Jurado, Nicole Puertas; Malek, Nisar P.; Goepel, Siri; Rosenberger, Peter; Häberle, Helene A.; Ayoub, Ikram; Al-Hajj, Sally; Nilsson, Jakob; Classen, Manfred; Liblau, Roland; Martin-Blondel, Guillaume; Bitzer, Michael; Roquilly, Antoine; Becher, Burkhard

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2-petides to the patients’ HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Towards clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.