The role of complement in COVID-19

我们分析了可公开获得的严重新冠肺炎患者肺部的scRNA-seq数据，发现在肺上皮细胞和肝细胞中，细胞固有补体的表达诱导是SARS-CoV2感染诱导最高的途径之一。此外，在患者的支气管肺泡灌洗细胞中，髓系、淋巴系和上皮细胞中的补体激活的明显特征与疾病的严重程度密切相关。对新冠肺炎诱导的宿主基因调节组的建模和能够使这些基因正常化的药物都涉及I型干扰素受体下游的JAK1/2-STAT1信号系统和NF-kB。JAK1/2抑制剂和最有希望的候选药物Ruxolitinib可以归一化干扰素信号基因、新冠肺炎中特征性最强的严重程度标志物IL-6和SARS-CoV2诱导的全部15个补体基因，但不影响NF-kB调节基因。我们预测，JAK抑制剂和其他有可能使NFkB信号正常化的药物，如抗病毒药物，联合治疗可能是一种有效的临床策略。 这篇稿件已被《科学免疫学》杂志接受。 此外，我们现在已经证明，CD46驱动的Th1关闭程序的失调(通过维生素D中间体的变化)有助于严重COVID患者肺中Th1的过度激活。

Our analysis of publically available scRNA-seq data from the lungs of patients with severe COVID-19 revealed that the expression induction of cell intrinsic complement is among the most highly induced pathways by SARS-CoV2 infection in lung epithelial and liver cells. Further, within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB. Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all 15 complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NFkB-signaling, such as anti-viral agents, may serve as an effective clinical strategy. This manuscript has been accepted by Science Immunology. In addition, we have now shown that dysregulation of the CD46-driven Th1 shut-down program (via changes in Vitamin D intermediates) contribute to Th1 hyperactivation in the lungs of patients with severe COVID.