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Regulatory Cross Talk Between SARS-CoV-2 Receptor Binding and Replication Machinery in the Human Host
Shiek S S J Ahmed1, Prabu Paramasivam2,3, Kamal Raj3
1Drug Discovery and Multi-Omics Laboratory, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, India.
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.
Insights
This study reveals how SARS-CoV-2 infects human lungs, identifying key proteins involved in viral replication. These findings highlight host vulnerabilities and suggest potential miRNA drug targets for COVID-19.
Area of Science:
- Virology
- Molecular Biology
- Network Biology
Background:
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, a global health crisis.
- Understanding the molecular mechanisms of SARS-CoV-2 pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To dissect the molecular mechanism of SARS-CoV-2 infection in the human lung.
- To identify host proteins and signaling pathways hijacked by the virus.
- To explore potential therapeutic targets for COVID-19.
Main Methods:
- Construction of two independent lung protein interactomes.
- Identification and functional analysis of hub proteins within the interactome networks.
- Analysis of correlations between viral replication proteins and comorbidities.
- Investigation of links with other coronavirus infections.
- Identification of interconnecting hubs and potential miRNA targets.
Main Results:
- SARS-CoV-2 infection differentially regulates key host proteins involved in viral replication.
- Proteins in viral replication hubs are associated with cardiovascular disease, diabetes, and hypertension, indicating increased severity in at-risk individuals.
- Hub proteins show connections to other coronavirus infections (MERS, HCoVs), suggesting conserved infection patterns.
- Five hub proteins interconnect the analyzed networks, facilitating viral replication upon receptor attachment.
- Seven potential microRNAs (miRNAs) targeting the intermediate phase of infection are identified as promising therapeutic candidates.
Conclusions:
- The study elucidates the intricate molecular interactions driving SARS-CoV-2 lung pathogenesis.
- Host protein hijacking and network hubs play critical roles in viral replication and disease severity.
- Identified miRNAs targeting key infection phases offer a novel therapeutic strategy against SARS-CoV-2.
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