ABSTRACT
The influence of SARS-CoV-2 non-structural protein in the host\'s tissue-specific complexities remains a mystery and needs more in-depth attention because of COVID-19 recurrence and long COVID. Here we investigated the influence of SARS-CoV-2 transmembrane protein NSP6 (Non-structural protein 6) in three major organs - the brain, heart, and lung in silico. To elucidate the interplay between NSP6 and host proteins, we analyzed the protein-protein interaction network of proteins interacting with NSP6 interacting proteins. Reported host interacting partners of NSP6 were ATP5MG, ATP6AP1, ATP13A3, and SIGMAR1. Pathway enrichment analyses provided global insights into biological pathways governed by differentially regulated genes in the three tissues after COVID-19 infection. Hub genes of tissue-specific protein interactome were analysed for drug targets and many were found. miRNA-gene network for the tissue-specific regulated proteins was sought. Comparing this list with the gene list targetted by SARS-CoV-2 regulated miRNAs, we found three and two common genes in the brain and lung respectively. Among the five common proteins revealed as potential therapeutic targets across the three tissues, four non-approved drugs and one approved drug could target Galectin 3 (LGALS3) and AIFM1 respectively. Increased expression of LGALS3 (that was upregulated in the heart after COVID-19 infection) is observed in multiple cancers and acts as a modulator for tumor progression. COVID-19 infection also causes myocardial inflammation and heart failure (HF). HF is observed to be increasing cancer incidence. The present scenario of long COVID-19 and recurrent COVID-19 infections warrants in-depth studies to probe the effect of COVID-19 infection on increased cancer incidence.
Subject(s)
Heart Failure , Neoplasms , COVID-19 , CardiomyopathiesABSTRACT
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, lung, and brain. We analysed SARS-CoV-2 ORF3a interacting host proteins in these three major organs. Further we identified common and unique interacting host proteins, their targeting miRNAs (lung and brain), and delineated associated biological processes reanalysing RNA-seq data from the brain (COVID-19 infected/uninfected Choroid Plexus Organoids 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. Number of unique ORF3a interacting proteins in brain, lung 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 heart was negative regulation of calcium ion transport. Reported observations of COVID-19 patients with the history of hypertension taking calcium channel blockers (CCBs) or dihydorpyridine CCBs had elevated rate of intubation or increased rate of intubation/death respectively. Also likelihood of hospitalization of chronic CCB users with COVID-19 was more 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 brain and lung revealed, 2 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.