COVID-19 ORF3a Viroporin-Influenced Common and Unique Cellular Signaling Cascades in Lung, Heart, and the Brain Choroid Plexus Organoids with Additional Enriched MicroRNA Network Analyses for Lung and the Brain Tissues

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.