SARS-CoV-2 induces "cytokine storm" hyperinflammatory responses in RA patients through pyroptosis.

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.

Zheng Q ，Lin R ，Chen Y ，Lv Q ，Zhang J ，Zhai J ，Xu W ，Wang W ... -  《Frontiers in Immunology》

IFI44 is an immune evasion biomarker for SARS-CoV-2 and Staphylococcus aureus infection in patients with RA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments. The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells. A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/β) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression. IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.

Zheng Q ，Wang D ，Lin R ，Lv Q ，Wang W ... -  《Frontiers in Immunology》

Quercetin is a Potential Therapy for Rheumatoid Arthritis via Targeting Caspase-8 Through Ferroptosis and Pyroptosis.

Zheng Q ，Wang D ，Lin R ，Chen Y ，Xu Z ，Xu W ... -  《Journal of Inflammation Research》

Key Genes Associated with Pyroptosis in Gout and Construction of a miRNA-mRNA Regulatory Network.

Bai B ，Liu Y ，Abudukerimu A ，Tian T ，Liang M ，Li R ，Sun Y ... -  《Cells》

Regulatory effect of zinc finger protein A20 on rheumatoid arthritis through NLRP3/Caspase-1 signaling axis mediating pyroptosis of HFLS- RA cells.

Zhao Z ，Ma X ，Dong S ，Yin H ，Yang Y ，Xiong G ... -  《-》