Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.

尽管 2019 年冠状病毒病 (COVID-19) 大流行在全球范围内产生了影响，但致命病毒性肺炎的潜在机制仍然难以捉摸。在这里，我们表明，与非危重病例相比，危重 COVID-19 与增强的嗜酸性粒细胞介导的炎症有关。此外，我们确认关键组中 T 辅助 (Th)2 偏向的适应性免疫反应增加，伴随着明显的补体激活。此外，增强的抗体反应和补体激活与疾病发病机制有关，这可以从六例致命病例的气道和肺活检血管系统中形成免疫复合物和膜攻击复合物来证明，以及通过增强来自关键 COVID-19 患者的呼吸道标本的骨髓细胞中 Fc 受体 (FcγR) 信号传导和补体激活的标志性基因组特征。这些结果表明，SARS-CoV-2 感染可能会驱动特定的先天免疫反应，包括嗜酸性粒细胞介导的炎症，以及随后通过增强的 Th2 偏向免疫反应引起的肺部发病机制，这可能是 COVID-19 患者重症的关键驱动因素。