Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Laboratory of Translational Genetics, Department of Human Genetics, VIB-KU Leuven, Leuven, Belgium.
Nat Commun. 2021 Jul 5;12(1):4117. doi: 10.1038/s41467-021-24360-w.
Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
流行病学和临床报告表明，SARS-CoV-2 的毒力取决于异常宿主免疫反应的触发，而不是直接的病毒诱导的细胞损伤。为了阐明 COVID-19 严重程度的免疫病理学基础，我们对 COVID-19 患者进行细胞因子和多重免疫分析。我们表明，COVID-19 中的细胞因子血症与巨噬细胞活化综合征中干扰素-γ驱动的细胞因子风暴不同，在重症 COVID-19 中比轻症-中度 COVID-19 更为明显。细胞因子水平的系统建模与深度免疫分析表明，经典单核细胞驱动这种高炎症表型，并且 T 淋巴细胞减少与疾病严重程度相关，CD8+细胞受到不成比例的影响。抗原呈递机制的表达在重症疾病中也降低。此外，我们报告说，中性粒细胞通过放大细胞因子血症和形成中性粒细胞胞外陷阱，导致疾病严重程度和局部组织损伤。综上所述，我们的研究结果表明存在一种髓样细胞驱动的免疫病理学，其中过度激活的中性粒细胞和无效的适应性免疫系统是 COVID-19 疾病严重程度的介导物。
