Kinome and phosphoproteome reprogramming underlies the aberrant immune responses in critically ill COVID-19 patients

The SARS-CoV-2 infection elicits comprehensive host immune reactions and causes severe diseases in some individuals. However, the molecular basis underlying the excessive, yet non-productive immune responses in severe COVID-19 is not fully understood. To address this, we compared the peripheral blood mononuclear cell (PBMC) proteome and phosphoproteome of sepsis patients positive or negative for SARS-CoV-2 and healthy subjects by quantitative mass spectrometry. We show here that the COVID-19 PBMC proteome and phosphoproteome undergo dynamic changes during disease progression, and the corresponding protein or phosphoprotein signatures can distinguish longitudinal disease states. Furthermore, SARS-CoV-2 infection leads to a global reprogramming of the kinome and the phosphoproteome, resulting in defective adaptive immune response mediated by B and T lymphocytes, compromised innate immune responses involving the SIGLEC and SLAM family of immunoreceptors, and excessive cytokine-JAK-STAT signaling. Besides uncovering the host proteome and phosphoproteome aberrations caused by SARS-CoV-2, our work has recapitulated several reported therapeutic targets for COVID-19 and identified numerous new ones, including the kinases PKG1, CK2, ROCK1/2, GRK2, SYK, JAK2/3, TYK2, DNA-PK and the cytokine IL-12. FUNDING. Ontario Research Fund (ORF)-COVID-19 Rapid Research Fund.