Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

Feyaerts D, Hedou J, Gillard J, Chen H, Tsai ES, Peterson LS, Ando K, Manohar M, Do E, Dhondalay GKR, Fitzpatrick J, Artandi M, Chang I, Snow TT, Chinthrajah RS, Warren CM, Wittman R, Meyerowitz JG, Ganio EA, Stelzer IA, Han X, Verdonk F, Gaudilliere DK, Mukherjee N, Tsai AS, Rumer KK, Jiang S, Valdes-Ferrer SI, Kelly JD, Furman D, Aghaeepour N, Angst MS, Boyd SD, Pinsky BA, Nolan GP, Nadeau KC, Gaudilliere B, McIlwain DR.


The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression.