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.

中文翻译：

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激酶组和磷酸化蛋白质组重编程是重症 COVID-19 患者异常免疫反应的基础

SARS-CoV-2 感染会引发广泛的宿主免疫反应，导致某些个体出现严重疾病。然而，严重的 COVID-19 中过度但非生产性免疫反应的分子基础仍不完全清楚。在本研究中，我们使用定量质谱法对 SARS-CoV-2 感染阳性或阴性的脓毒症患者以及健康受试者的外周血单核细胞 (PBMC) 蛋白质组和磷酸蛋白质组进行了全面分析。我们的研究结果表明，在疾病进展过程中，COVID-19 PBMC 蛋白质组和磷酸蛋白质组发生动态变化，具有能够区分纵向疾病状态的独特蛋白质或磷蛋白特征。此外，SARS-CoV-2感染诱导激酶组和磷酸蛋白质组的整体重编程，导致B和T淋巴细胞介导的适应性免疫反应缺陷，涉及免疫受体SIGLEC和SLAM家族的先天免疫反应受损，以及过多的细胞因子-JAK -STAT信号。除了揭示 SARS-CoV-2 引起的宿主蛋白质组和磷酸蛋白质组畸变外，我们的工作还概括了多个已报告的 COVID-19 治疗靶点，并确定了许多新的候选激酶，包括激酶 PKG1、CK2、ROCK1/2、GRK2、SYK、JAK2 /3、TYK2、DNA-PK、PKCδ 和细胞因子 IL-12。