Immunogenic Cell Death Involves in SARS-CoV-2 and Pulmonary Arterial Hypertension Crosstalk

Abstract

Background: Pulmonary arterial hypertension (PAH) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that individuals with PAH are at substantial risk for rapid deterioration once infected. However, the underlying mechanism and genetic signatures of PAH and SARTS-CoV-2 remains unclear.

Methods: The PAH and SARS-CoV-2 datasets were downloaded from the Gene Expression Omnibus (GEO) database, immunogenic cell death (ICD) genes were extracted, and differential expression analysis was performed to obtain shared differentially expressed genes (DEGs). Meta-analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analysis were performed on DEGs to observe functional enrichment of these genes and associations between genes. The disease prediction model was constructed by artificial neural network (ANN), and its accuracy was further evaluated by receiver operating characteristic (ROC) curve. Using Single-sample GSEA (ssGSEA) to evaluate the correlation between disease signature genes and immune cell abundance in the PAH dataset and the SARS-CoV-2 dataset. Finally, the screened drugs were predicted by DEGs, and were molecularly docked with DEGs by AutoDock Vina.

Findings: TLR4, MYD88, IL1B, and HMGB1 four shared genes were identified by ICD differential gene expression analysis. NF-kappa B signaling pathway, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway closely related to inflammation were observed by the enrichment analysis of DEGs. The result of immune infiltration showed that these DEGs were involved in the changes of PAH and the immune microenvironment of SARS-CoV-2, and the same regulatory process existed in Macrophage, Monocyte, Central memory CD8 T cell, and Central memory CD4 T cell. Nitric oxide, Resveratrol, and Curcumin may promise drugs for the treatment of SARS-CoV-2 and PAH. Further verification of Resveratrol and Curcumin by molecular docking showed that Resveratrol and Curcumin have good docking activity with their target proteins.

Interpretation: Analogous molecular mechanism between PAH and SARS-CoV-2 from the perspective of ICD. The key genes IL1B, MYD88, TLR4 and HMGB1 involve in the immune cell response process, thus affecting the progression of these two diseases. These findings may provide novel directions for treatment of PAH and SARS-CoV-2.