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New Ways to Protect the Host from SARS-CoV-2? Lung Microbiome Metabolites Inhibit STAT3 and Modulate the
Jency Roshni1, Mahema Sivakumar1, Faris Ahmed Bahammam2
1Drug Discovery and Multi-omics Lab, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India.
Abstract:
COVID-19 caused by the SARS-CoV-2 infection is a systemic disease that affects multiple organs, biological pathways, and cell types. A systems biology approach would benefit the study of COVID-19 in the pandemic as well as the endemic state. Notably, patients with COVID-19 have dysbiosis of lung microbiota whose functional relevance to the host is largely unknown. We carried out a systems biology investigation of the impact of lung microbiome-derived metabolites on host immune system during COVID-19. RNAseq was performed to identify the host-specific pro- and anti-inflammatory differentially expressed genes (DEGs) in bronchial epithelium and alveolar cells during SARS-CoV-2 infection. The overlapping DEGs were harnessed to construct an immune network while their key transcriptional regulator was deciphered. We identified 68 overlapping genes from both cell types to construct the immune network, and Signal Transducer and Activator of Transcription 3 (STAT3) was found to regulate the majority of the network proteins. Furthermore, thymidine diphosphate produced from the lung microbiome had the highest affinity with STAT3 (-6.349 kcal/mol) than the known STAT3 inhibitors (n = 410), with an affinity ranging from -5.39 to 1.31 kcal/mol. In addition, the molecular dynamic studies showed distinguishable changes in the behavior of the STAT3 complex when compared with free STAT3. Overall, our results provide new observations on the importance of lung microbiome metabolites that regulate the host immune system in patients with COVID-19, and may open up new avenues for preventive medicine and therapeutics innovation.
Insights
Lung microbiome metabolites impact the COVID-19 immune response. Thymidine diphosphate showed high affinity with STAT3, suggesting new therapeutic targets for COVID-19 treatment.
Area of Science:
- Systems biology and immunology
- Microbiome research
- Infectious disease
Background:
- COVID-19 is a systemic disease affecting multiple organs and pathways.
- Lung microbiota dysbiosis is observed in COVID-19 patients, but its role is unclear.
- A systems biology approach is needed to understand COVID-19's complexity.
Purpose of the Study:
- To investigate the impact of lung microbiome metabolites on the host immune system during COVID-19.
- To identify key regulators of the host immune response in bronchial and alveolar cells.
Main Methods:
- RNA sequencing (RNAseq) to identify differentially expressed genes (DEGs) in response to SARS-CoV-2.
- Construction of an immune network using overlapping DEGs from bronchial and alveolar cells.
- Computational analysis including molecular docking and molecular dynamics to assess metabolite-protein interactions.
Main Results:
- Identified 68 overlapping DEGs, with Signal Transducer and Activator of Transcription 3 (STAT3) regulating most.
- Lung microbiome-derived thymidine diphosphate exhibited higher binding affinity to STAT3 than known inhibitors.
- Molecular dynamics revealed significant changes in the STAT3 complex behavior upon binding.
Conclusions:
- Lung microbiome metabolites play a crucial role in modulating the host immune system during COVID-19.
- Thymidine diphosphate emerges as a potential modulator of STAT3 activity in COVID-19.
- Findings suggest novel avenues for preventive medicine and therapeutic innovation targeting the lung microbiome.
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