Systems-Wide View of Host-Pathogen Interactions Across COVID-19 Severities Using Integrated Omics Analysis

The SARS-CoV-2 pandemic has caused millions of deaths worldwide. The pathogenesis of COVID-19 is complex and the mechanisms associated with variable clinical manifestations including mild, moderate and severe diseases are not fully understood. We used an integrated approach combining host-pathogen protein-protein interaction data and viral-induced host gene expression data to understand pathogenesis and identify key gene expression markers associated with COVID-19 disease severity. We analyzed RNA-Seq data of peripheral blood mononuclear cells (PBMCs) of 1960 samples from 12 projects under different disease severities, and identified genes that were differentially expressed in mild, moderate, and severe conditions. Enrichment analysis of the pathways in host proteins targeted by each of the 49 SARS-CoV-2 proteins revealed a strong association with processes related to ribosomal biogenesis, translation, and translocation. Intriguingly, most of these pathways and related cellular components, including ribosomal biogenesis, ribosomal proteins, and translation, were upregulated in mild conditions but downregulated in severe conditions. This suggests that in severe covid-19, host's respond by shutting down the translation pathways exploited by viruses which may help to prevent the virus from replicating and may also potentially compromise essential host cellular functions such as protein synthesis, the host's ability to mount an effective antiviral response, and causing broader health implications.