The role of complement in COVID-19

补体在 COVID-19 中的作用

• 批准号: 10699747
• 负责人: Claudia Kemper
• 金额: $ 7.96万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699747
• 关键词: 2019-nCoV; Acute; Affect; Antiviral Agents; Bronchoalveolar Lavage; CD46 Antigen; COVID-19; COVID-19 pathogenesis; COVID-19 patient; Cells; Clinical; Combined Modality Therapy; Complement; Complement Activation; Data; Disease; Epithelial Cells; Genes; Hepatocyte; Immune; Immunology; Interferons; Interleukin-6; JAK1 gene; Kidney; Liver; Long COVID; Lung; Lung infections; Lymphoid Cell; Manuscripts; Modeling; Myeloid Cells; NF-kappa B; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pulmonary Inflammation; Role; SARS-CoV-2 infection; STAT1 gene; Science; Severities; Severity of illness; Signal Transduction; System; Vitamin D; alveolar type II cell; coronavirus disease; gene complementation; genetic signature; inhibitor; programs; severe COVID-19; single-cell RNA sequencing; type I interferon receptor

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.

我们对来自严重COVID-19患者肺部的可获得的scRNA-seq数据的分析表明，细胞内在补体的表达诱导是肺上皮细胞和肝细胞中SARS-CoV 2感染最高度诱导的途径之一。此外，在患者的支气管肺泡灌洗液的细胞内，骨髓、淋巴和上皮细胞中补体激活的不同特征与疾病严重程度一起追踪。对COVID-19诱导的宿主基因的调节组进行建模以及可以使这些基因正常化的药物都涉及I型干扰素受体下游的JAK 1/2-STAT 1信号系统和NF-κ B。鲁索利替尼是JAK 1/2抑制剂，也是预测最高的候选药物，可以使干扰素标签基因、IL-6（COVID-19中最具特征的严重程度标志物）和SARS-CoV 2诱导的所有15种补体基因正常化，但不影响NF-kB调控的基因。我们预测，JAK抑制剂和其他有可能使NF κ B信号正常化的药物（如抗病毒药物）的联合治疗可能是一种有效的临床策略。 该手稿已被《科学免疫学》接受。 此外，我们现在已经表明，CD 46驱动的Th 1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患者肺部的Th 1过度激活。