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. 2020 Jun 30:11:802.
doi: 10.3389/fphys.2020.00802. eCollection 2020.

Regulatory Cross Talk Between SARS-CoV-2 Receptor Binding and Replication Machinery in the Human Host

Shiek S S J Ahmed  1 , Prabu Paramasivam  2   3 , Kamal Raj  3 , Vishal Kumar  4 , Ram Murugesan  1 , V Ramakrishnan  5
Affiliations

Regulatory Cross Talk Between SARS-CoV-2 Receptor Binding and Replication Machinery in the Human Host

Shiek S S J Ahmed et al. Front Physiol. .

Abstract

We dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. Two independent lung protein interactome were constructed to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from the interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins in viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five hubs that interconnect both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

Keywords: Covid-19; SARS-CoV-2; host mechanism; miRNA targets; systems biology; transcriptome.

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Figures

Figure 1
Figure 1
A strategic workflow diagram representing the step-wise processes of this study. Eight interdependent steps were followed, that majorly involved collection, classification, mapping, and data analysis. Each step was self-explained with the legend describing the process within the workflow.
Figure 2
Figure 2
Receptor-mediated network. The protein interaction network describing the protein connectivity between the host and SARS CoV2. The three red color nodes represent the SARS CoV2 surface proteins interacting (black dotted) with the seed proteins, STOM, ATP6V1A, AP3B1, and ZDHNNC5, a host protein (violet) localized at the cell surface. All four seed proteins mediated it signals to its interacting proteins (green) and form a four individual closed hub.
Figure 3
Figure 3
Molecular enrichment of receptor hubs. Enrichment of hubs showing major involvement of immune system, metabolism, and signal transduction. Significant involvement of hemostasis, transcription machinery, transport of small molecules, cellular response to external stimuli, protein metabolism, and vesicle-mediated transport. Over-representation of these molecular events suggests host self-defense mechanism and preparation of the optimal environment in the host for the viral replication process on receptor attachment.
Figure 4
Figure 4
Enrichment of hubs derived from virus replication machinery network. Enrichment of 325 proteins in eleven hubs showing the wide coverage of involvement in the immune system, signal transduction and active involvement of transcription machinery, protein metabolism, cell cycle, metabolism, DNA replication, DNA repair, metabolism, programmed cell death, and cellular response to external stimuli.
Figure 5
Figure 5
Protein interconnectivity between the functional hubs. The hub network of AP3B1 hub (green node) and hub 4 (violet node) demonstrating the interconnecting proteins between (red dotted edges) the hubs. The yellow nodes represent the viral protein interaction with the hubs. The viral envelope interacts with host AP3B1 surface protein that activates a series of proteins leading to utilization for viral machinery propose of orf10, nsp1, and 9. Additionally, the red highlighting node represents the differentially expressed genes on SARS-CoV2 infection derived from RNA-Seq analysis.
Figure 6
Figure 6
Interconnectivity between the functional hubs. The hub network of STOM hub (green node) and hub 4 (violet node) demonstrating the interconnecting proteins between (red dotted edges) the hubs. The yellow nodes represent the viral protein interaction with the hubs. The viral membrane interacts with host STOM surface protein that activates the series of proteins leading to utilization for viral machinery propose of orf10, nsp1, and 9. Additionally, the red highlighting node represents the differentially expressed genes on SARS-CoV2 infection derived from RNA-Seq analysis.
Figure 7
Figure 7
Interconnectivity between the functional hubs. The hub network of STOM hub (green node) and hub 7 (violet node) demonstrating the interconnecting proteins between (red dotted edges) the hubs. The yellow nodes represent the viral protein interacting with the hubs. The viral membrane interacts with host STOM surface protein that activates the series of proteins leading to benefit viral machinery relating to nucleocapsid and nsp15. Additionally, the red highlighting node represents the differentially expressed genes on SARS-CoV2 infection derived from RNA-Seq analysis.
Figure 8
Figure 8
Functional hubs interconnectivity. The hub network of ATP6V1A hub (green node) and hub 5 (violet node) demonstrating the interconnecting proteins between (red dotted edges) the hubs. The yellow nodes represent the viral protein interacting with the hubs. The viral membrane interacts with host ATP6V1A surface protein that activates the series of proteins leading to benefit viral machinery relating to nsp7 and nsp11. The red highlighting node represents the differentially expressed genes on SARS-CoV2 infection derived from RNA-Seq analysis.
Figure 9
Figure 9
Functional hubs interconnectivity. The hub network of ATP6V1A hub (green node) and hub 5 (violet node) demonstrating the interconnecting proteins between (red dotted edges) the hubs. The yellow nodes represent the viral protein interacting with the hubs. The viral envelope interacts with host ATP6V1A surface protein that activates the series of proteins leading to benefit viral machinery relating to nucleocapsid and nsp15. Additionally, the red highlighting node represents the differentially expressed genes on SARS-CoV2 infection derived from RNA-Seq analysis.
Figure 10
Figure 10
Enrichment of interconnecting hub proteins. Enrichment of 34 proteins from five interconnected hubs showing the contribution in the immune system, signal transduction, transcription machinery, and protein metabolism. These interconnecting mechanisms suggest being the intermediate phase that connects the events between early host attachment and the viral replication process.
Figure 11
Figure 11
miRNA network. The network demonstrates the miRNA (yellow node) target for (black dotted edges) 34 protein encoding genes (while ellipse). The miRNA (red highlighted node) that inhibits (bold edges) more than three genes (green ellipse) interconnecting hub proteins are represented. These miRNAs will be the potential molecule as a drug that helps in inhibition of connective between host attachment and the viral replication process.
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