New Ways to Protect the Host from SARS-CoV-2? Lung Microbiome Metabolites Inhibit STAT3 and Modulate the Immunological Network

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.