Blood transcriptome analysis revealed the crosstalk between severe COVID-19 and systemic lupus erythematosus

Dear editor, We have read with great interest the article by Cui et al. that previously reported the correlation between high inflammasome expression and pyroptosis with severe COVID-19 infection in cancer patients.1Cui H. Liu J. Zhang L. The high expression of key components of inflammasome and pyroptosis might lead to severe COVID-19 infection in cancer patients.J Infect. 2022; 84: e19-e21Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar We noticed that activation of inflammasome and pyroptosis also function in systemic lupus erythematosus (SLE).2Kong R. Sun L. Li H. Wang D. The role of NLRP3 inflammasome in the pathogenesis of rheumatic disease.Autoimmunity. 2022; 55: 1-7Crossref PubMed Scopus (17) Google Scholar, 3Shin J.I. Lee K.H. Joo Y.H. Lee J.M. Jeon J. Jung H.J. et al.Inflammasomes and autoimmune and rheumatic diseases: a comprehensive review.J Autoimmun. 2019; 103102299Crossref PubMed Scopus (59) Google Scholar Recently, several studies have reported that patients with SLE might have a higher risk of severe COVID-19, and the risk of SLE was substantially higher in COVID-19 individuals.4Ugarte-Gil M.F. Alarcón G.S. Izadi Z. Duarte-García A. Reátegui-Sokolova C. Clarke A.E. et al.Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance.Ann Rheum Dis. 2022; 81: 970-978Crossref PubMed Scopus (31) Google Scholar, 5Chang R. Yen-Ting Chen T. Wang S.-I. Hung Y.-M. Chen H.-Y. Wei C.-C.J. Risk of autoimmune diseases in patients with COVID-19: a retrospective cohort study.EClinicalMedicine. 2023; 56101783Abstract Full Text Full Text PDF Scopus (7) Google Scholar, 6Yang H. Xu J. Liang X. Shi L. Wang Y. Autoimmune diseases are independently associated with COVID-19 severity: evidence based on adjusted effect estimates.J Infect. 2021; 82: e23-e26Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Severe COVID-19 and SLE seem to have a strong connection; however, the potential molecular mechanisms are unclear. In this study, we used blood transcriptome analysis to explore the potential mechanisms and key genes hiding in the crosstalk between severe COVID-19 and SLE. Two severe COVID-19 datasets (GSE164805 and GSE171110) and one SLE dataset (GSE45291) were downloaded from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/) and then analyzed. We selected 4920 differentially expressed genes (DEGs), including 2310 upregulated genes and 2610 downregulated genes, from 54 patients suffering from severe COVID-19 (Fig. 1A). Furthermore, a total of 1448 DEGs, including 377 upregulated genes and 694 downregulated genes, were identified from 292 SLE patients (Fig. 1B). We then took the intersection of the selected DEGs, and a total of 272 genes were obtained (Fig. 1C). To reveal the potential functions of those DEGs, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. For enrichment of GO terms, the shared DEGs were mainly involved in the immune system process, multi-organism pathway, immune response, and transcription factor binding and related to cytosol and mitochondrion (Fig. 1D). For KEGG pathway enrichment analysis, the top five significant pathways were Cytokine-cytokine receptor interaction, influenza A, Th17 cell differentiation, Epstein-Barr virus infection, and ribosome (Fig. 1E). To further identify key genes affecting the interactions between severe COVID-19 and SLE, we used STRING (https://string-db.org/) and Cytoscape to screen the top 20 hub genes using six topological algorithms of the plugin CytoHubba and obtained their intersection (Fig. 2A). The final 17 hub genes included IFIT3, RSAD2, IFIT1, IFI44L, IFI44, OAS3, OAS1, OAS2, IFIT2, IFI35, OASL, IFI27, IFIT5, XAF1, USP18, HERC5, and EIF2AK2. GO enrichment analysis showed that these genes functioned in the defense response, innate immune response, biotic stimulus response, and infection response, and were mainly related to the cytosol and RNA binding (Fig. 2B). KEGG pathway enrichment analysis revealed that these genes were mainly involved in immune- and infection-related pathways such as Hepatitis C and NOD-like receptor signaling pathways (Fig. 2C). In addition, we verified the expression of these 17 DEGs in the severe COVID-19 and SLE datasets. Interestingly, all these key genes were significantly highly expressed in both the severe COVID-19 cohorts and the SLE cohort compared to those in healthy individuals (Fig. 2D and E). Furthermore, we constructed a transcription factor (TF)-miRNA-hub gene network to present potential regulatory mechanisms by NetworkAnalyst.7Zhou G. Soufan O. Ewald J. Hancock R.E.W. Basu N. Xia J. NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis.Nucleic Acids Res. 2019; 47: W234-W241Crossref PubMed Scopus (732) Google Scholar The network consists of 72 nodes and 78 edges, including 41 TFs, 21 miRNAs, and 10 key genes (Fig. 2F). Our work identified some key genes and presented molecular mechanisms of the correlation between severe COVID-19 and SLE. Notably, most selected genes belong to interferon-induced proteins with tetratricopeptide repeats (IFITs) or oligoadenylate synthetase (OAS) gene families. IFITs and OAS gene families are both induced by Interferons (IFNs), participate in regulating innate immune response, and play antiviral functions.8Hornung V. Hartmann R. Ablasser A. Hopfner K.-P. OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids.Nat Rev Immunol. 2014; 14: 521-528Crossref PubMed Scopus (188) Google Scholar, 9Zhou X. Michal J.J. Zhang L. Ding B. Lunney J.K. Liu B. et al.Interferon induced IFIT family genes in host antiviral defense.Int J Biol Sci. 2013; 9: 200-208Crossref PubMed Scopus (155) Google Scholar Previous research has proven that IFNs and the innate immune response are involved in the progression of COVID-19 and SLE. The dysregulation of IFNs and perturbations in adaptive immune systems, which is prevalent in SLE, may lead to severe COVID-19.10Thanou A. Sawalha A.H. SARS-CoV-2 and systemic lupus erythematosus.Curr Rheumatol Rep. 2021; 23: 8Crossref PubMed Scopus (13) Google Scholar In short, our results revealed potential mechanisms and key biomarkers that contribute to the crosstalk between severe COVID-19 and SLE, which provides new insight into COVID-19 and SLE and contributes to precise diagnosis and treatment. This work was funded by the National College Students’ Innovation and Entrepreneurship Training Program (No. 202210366002) and the College Students’ Innovation and Entrepreneurship Training Program of Anhui Province (No. S202210366021 and S202210366017).