COVID-19 ORF3a Viroporin-Influenced Common and Unique Cellular Signaling Cascades in Lung, Heart, and the Brain...

Tissue-specific implications of SARS-CoV-2-encoded accessory proteins are not fully understood. SARS-CoV-2 infection can severely affect three major organs-the heart, lungs, and brain. We analyzed SARS-CoV-2 ORF3a interacting host proteins in these three major organs. Furthermore, we identified common and unique interacting host proteins and their targeting miRNAs (lung and brain) and delineated associated biological processes by reanalyzing RNA-seq data from the brain (COVID-19-infected/uninfected choroid plexus organoid study), lung tissue from COVID-19 patients/healthy subjects, and cardiomyocyte cells-based transcriptomics analyses. Our in silico studies showed ORF3a interacting proteins could vary depending upon tissues. The number of unique ORF3a interacting proteins in the brain, lungs, and heart were 10, 7, and 1, respectively. Though common pathways influenced by SARS-CoV-2 infection were more, unique 21 brain and 7 heart pathways were found. One unique pathway for the heart was negative regulation of calcium ion transport. Reported observations of COVID-19 patients with a history of hypertension taking calcium channel blockers (CCBs) or dihydropyridine CCBs had an elevated rate of intubation or increased rate of intubation/death, respectively. Also, the likelihood of hospitalization of chronic CCB users with COVID-19 was greater in comparison to long-term angiotensin-converting enzyme inhibitors/angiotensin receptor blockers users. Further studies are necessary to confirm this. miRNA analysis of ORF3a interacting proteins in the brain and lungs revealed 3 of 37 brain miRNAs and 1 of 25 lung miRNAs with high degree and betweenness indicating their significance as hubs in the interaction network. Our study could help in identifying potential tissue-specific COVID-19 drug/drug repurposing targets.