The role of complement in COVID-19

我们对来自严重COVID-19患者肺部的公开可用scRNA-seq数据的分析显示，细胞内在补体的表达诱导是SARS-CoV2感染在肺上皮细胞和肝细胞中诱导程度最高的途径之一。此外，在患者支气管肺泡灌洗的细胞中，骨髓、淋巴和上皮细胞中补体活化的明显特征与疾病严重程度有关。模拟COVID-19诱导的宿主基因的规则组以及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。Ruxolitinib， JAK1/2抑制剂和预测最高的候选药物，正常化干扰素标记基因，IL-6 （COVID-19中最具特征的严重程度标记物）和SARS-CoV2诱导的所有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。

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 is currently under review and uploaded onto MedRxic.org