Department of Orthopedics, 900th Hospital of Joint Logistics Support Force, Fuzhou, China.
Department of Paediatrics, Fujian Provincial Hospital South Branch, Fuzhou, China.
Front Immunol. 2022 Dec 1;13:1058884. doi: 10.3389/fimmu.2022.1058884. eCollection 2022.
The coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.
We obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.
COVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.
Caspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.
冠状病毒病（COVID-19）是一种威胁全球公共卫生的大流行病，类风湿关节炎（RA）是最常见的自身免疫性疾病。COVID-19 和 RA 都是彼此的强危险因素，但它们的分子机制尚不清楚。本研究旨在从细胞焦亡的机制探讨 COVID-19 和 RA 之间的生物标志物，并寻找有效的疾病靶向药物。
我们使用生物信息学分析从 COVID-19、RA（GSE55235）和细胞焦亡中获得共同基因，然后进行主成分分析（PCA）。使用基因本体论（GO）、京都基因与基因组百科全书（KEGG）和 ClueGO 评估共基因的功能富集，通过 STRING 构建蛋白质-蛋白质相互作用（PPI）网络，使用 k-均值机器学习算法进行聚类分析。使用 Cytoscape 进行模块分析以识别枢纽基因，使用 Metascape 和 GeneMANIA 进行功能富集分析，使用 NetworkAnalyst 进行基因-药物预测。通过网络药理学分析鉴定与 COVID-19、RA 和细胞焦亡相关的靶药物相关基因，以获得共枢纽基因，并通过 NetworkAnalyst 构建转录因子（TF）-枢纽基因和 miRNA-枢纽基因网络。使用 GSE55457 和 GSE93272 验证共枢纽基因，以获得关键基因，并使用接收者操作曲线（ROC）评估其疗效；然后使用 SPEED2 确定上游途径。使用 CIBERSORT 分析免疫细胞浸润，并使用 HPA 数据库进行验证。通过计算机辅助药物设计，使用分子对接、分子动力学模拟和分子力学-广义 Born 表面积（MM-GBSA）探索和验证药物-基因关系。
COVID-19、RA 和细胞焦亡相关基因在细胞焦亡和促炎途径（含 NOD 样受体家族包含 pyrin 域的 3（NLRP3）炎性小体复合物、死亡诱导信号复合物、白细胞介素产生的调节）、天然免疫途径（SARS-CoV-2 信号通路网络图谱、SARS-CoV-2 激活 NLRP3 炎性小体）和 COVID-19 和 RA 相关细胞因子风暴途径（IL、核因子-κB（NF-κB）、TNF 信号通路和细胞因子介导的信号转导的调节）中富集。其中，CASP1 是最相关的途径，与米诺环素密切相关。YY1、hsa-mir-429 和 hsa-mir-34a-5p 在 CASP1 的表达中起重要作用。单核细胞是高半胱氨酸酶-1 表达的哨兵细胞。米诺环素可以通过与半胱氨酸蛋白酶-1 的活性区域紧密结合，产生生化活性的高度稳定状态。
Caspase-1 是 COVID-19、RA 和细胞焦亡的共同生物标志物，它可能通过细胞焦亡成为 SARS-CoV-2 在 RA 患者中诱导过度炎症反应的重要介质。米诺环素可能通过抑制半胱氨酸蛋白酶-1 的表达来抑制 COVID-19 合并 RA 患者的细胞因子风暴炎症。
