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. 2023 Nov 17;8(48):45817-45833.
doi: 10.1021/acsomega.3c06485. eCollection 2023 Dec 5.

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

Soura Chakraborty  1 , Shrabonti Chatterjee  2 , Subhashree Mardi  2 , Joydeep Mahata  2 , Suneel Kateriya  1 , Pradeep Punnakkal  3 , Gireesh Anirudhan  2
Affiliations

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

Soura Chakraborty et al. ACS Omega. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Network presentation of regulated common proteins expressed in the brain, lungs, and heart after SARS-CoV-2 infection. Visualization done in Cytoscape.
Figure 2
Figure 2
Top 10 hub genes of the common protein networks of regulated proteins after SARS-CoV-2 infection in the brain, lungs, and heart. Regulated proteins common in the brain, lungs, and heart were analyzed by cytoHubba to find the top 10 hub genes (shown separately from the circularly arranged proteins). Node color from red to yellow represents higher to lower significance. NOTCH1, HRAS, STAT3, and ESR1 are highly significant major hub genes.
Figure 3
Figure 3
MCODE analysis of protein–protein interactome representing the top five clusters. All five clusters are highly connected and each cluster is represented by a different color. Individual clusters are depicted in Figures S1 to S5.
Figure 4
Figure 4
Venn diagram showing the number of biological pathways associated with ORF3a interacting proteins in the heart, lung, and brain. 44 pathways are common in the heart, lungs, and brain. 21 unique pathways were observed in the brain, whereas in the heart, 7 were present. No unique pathway was observed in the lungs.
Figure 5
Figure 5
SARS-CoV-2 ORF3a regulated common pathways in the lung, heart, and brain. The dot size represents the gene ratio and the dot color depicts the p.adjust value as in the heat map.
Figure 6
Figure 6
SARS-CoV-2 ORF3a regulates unique pathways in the brain. Dot size represents the gene ratio and dot color depicts the p-value as in the heat map.
Figure 7
Figure 7
SARS-CoV-2 ORF3a regulates unique pathways in the heart. Dot size represents the gene ratio and dot color depicts the p-value as in the heat map.
Figure 8
Figure 8
Dot plot of enriched GO terms of differentially expressed genes in the brain. The Y-axis indicates the GO term and the X-axis shows the count of genes per GO term. The color gradient indicates the p-value, using the Benjamini–Hochberg method. (a) Upregulated genes and (b) downregulated genes.
Figure 9
Figure 9
Dot plot of enriched GO terms of differentially expressed genes in the heart. The Y-axis indicates the GO term and the X-axis shows the count of genes per GO term. The color gradient indicates the p-value, using the Benjamini–Hochberg method. (a) Upregulated genes and (b) downregulated genes.
Figure 10
Figure 10
Dot plot of enriched GO terms of differentially expressed genes in the lung. The Y-axis indicates the GO term and the X-axis shows the count of genes per GO term. The color gradient indicates the p-value, using the Benjamini–Hochberg method. (a) Upregulated genes and (b) downregulated genes.
Figure 11
Figure 11
miRNA interaction network with SARS-CoV-2 ORF3a binding 8 proteins in the brain. Circles represent ORF3a binding proteins, and squares represent miRNAs. The increased size of nodes represents a higher degree. For miRNA, darker shades of continuous mapping of node color represent higher significance (dark green to yellow).
Figure 12
Figure 12
miRNA interaction network with SARS-CoV-2 ORF3a binding 8 proteins in the lung. Circles represent ORF3a binding proteins, and squares represent miRNAs. The increased size of nodes represents a higher degree. For miRNA, darker shades of continuous mapping of node color represent higher significance (dark green to yellow).
Figure 13
Figure 13
SARS-CoV-2-influenced miRNA—protein network in the brain. Common miRNAs in the reported list of SARS-CoV-2-influenced circulating miRNAs and the miRNAs that can target brain-expressing interacting partners of SARS-CoV-2 ORF3a interacting partners were taken for analysis. Proteins taken for analysis were SARS-CoV-2-influenced by SARS-CoV-2 ORF3a interacting proteins expressed in the brain. Nodes in circles are proteins, and nodes in squares are miRNAs.
Figure 14
Figure 14
SARS-CoV-2-influenced miRNA—protein network in the lung. Common miRNAs in the reported list of SARS-CoV-2-influenced circulating miRNAs and the miRNAs that can target lung-expressing interacting partners of SARS-CoV-2 ORF3a interacting partners were taken for analysis. Proteins taken for analysis were SARS-CoV-2-influenced by SARS-CoV-2 ORF3a interacting proteins expressed in the lung. Nodes in circles are proteins, and nodes in squares are miRNAs.
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