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

• Published in: Clinical proteomics Vol. 21; no. 1; p. 13
• Main Authors: Kaneko, Tomonori, Ezra, Sally, Abdo, Rober, Voss, Courtney, Zhong, Shanshan, Liu, Xuguang, Hovey, Owen, Slessarev, Marat, Van Nynatten, Logan Robert, Ye, Mingliang, Fraser, Douglas D., Li, Shawn Shun-Cheng
• Format: Journal Article
• Language: English
• Published: London BioMed Central 22.02.2024; BioMed Central Ltd
• Subjects: Adaptive immunity; Analysis; B cells; b-Adrenergic-receptor kinase; Biomedical and Life Sciences; Biotechnology; Cell Biology; COVID-19; Cytokines; Development and progression; Disease; Disease susceptibility; DNA-dependent protein kinase; Ethanol; Health aspects; Hemoglobin; Immune response; Immunology; Infection; Infections; Innate immunity; Intensive care; Janus kinase 2; Labeling; Life Sciences; Lymphocytes; Lymphocytes T; Mass spectrometry; Mass spectroscopy; Pathology; Peptides; Peripheral blood mononuclear cells; Proteins; Proteomes; Proteomics; Scientific imaging; Sepsis; Severe acute respiratory syndrome coronavirus 2; Syk protein; T cells; Testing laboratories; Therapeutic targets; Tyk2 protein; COVID-19; SARS-CoV-2; Kinome reprogramming; Tandem mass tag; Cytokine; Proteome; Phosphoproteome; Immune regulation; Mass spectrometry; Antibody response
• ISSN: 1542-6416; 1559-0275
• DOI: 10.1186/s12014-024-09457-w

SARS-CoV-2 infection triggers extensive host immune reactions, leading to severe diseases in certain individuals. However, the molecular basis underlying the excessive yet non-productive immune responses in severe COVID-19 remains incompletely understood. In this study, we conducted a comprehensive analysis of the peripheral blood mononuclear cell (PBMC) proteome and phosphoproteome in sepsis patients positive or negative for SARS-CoV-2 infection, as well as healthy subjects, using quantitative mass spectrometry. Our findings demonstrate dynamic changes in the COVID-19 PBMC proteome and phosphoproteome during disease progression, with distinctive protein or phosphoprotein signatures capable of distinguishing longitudinal disease states. Furthermore, SARS-CoV-2 infection induces a global reprogramming of the kinome and phosphoproteome, resulting in defective adaptive immune response mediated by the B and T lymphocytes, compromised innate immune responses involving the SIGLEC and SLAM family of immunoreceptors, and excessive cytokine-JAK-STAT signaling. In addition to uncovering host proteome and phosphoproteome aberrations caused by SARS-CoV-2, our work recapitulates several reported therapeutic targets for COVID-19 and identified numerous new candidates, including the kinases PKG1, CK2, ROCK1/2, GRK2, SYK, JAK2/3, TYK2, DNA-PK, PKCδ, and the cytokine IL-12.