Abstract
BackgroundSARS-CoV-2 causes ongoing pandemic coronavirus disease of 2019 (COVID-19), infects the cells of the lower respiratory tract that leads to a cytokine storm in a significant number of patients resulting in severe pneumonia, shortness of breathing, respiratory and organ failure. Extensive studies suggested the role of Vitamin D in suppressing cytokine storm in COVID-19 and reducing viral infection; however, the precise molecular mechanism is not clearly known. In this work, bioinformatics and systems biology approaches were used to understand SARS-CoV-2 induced cytokine pathways and the potential mechanism of Vitamin D in suppressing cytokine storm and enhancing antiviral response.ResultsThis study used transcriptome data and identified 108 differentially expressed host genes (DEHGs) in SARS-CoV-2 infected normal human bronchial epithelial (NHBE) cells compared to control. Then, the DEHGs was integrated with the human protein-protein interaction data to generate a SARS-CoV-2 induced host gene regulatory network (SiHgrn). Analysis of SiHgrn identified a sub-network “Cluster 1” with the highest MCODE score, 31 up-regulated genes, and predominantly associated immune and inflammatory response. Interestingly, the iRegulone tool identified that “Cluster 1” is under the regulation of transcription factors STAT1, STAT2, STAT3, POU2F2, and NFkB1, collectively referred to as “host response signature network”. Functional enrichment analysis with NDEx revealed that the “host response signature network” is predominantly associated with critical pathways, including “cytokines and inflammatory response”, “non-genomic action of Vitamin D”, “the human immune response to tuberculosis”, and “lung fibrosis”. Finally, in-depth analysis and literature mining revealed that Vitamin D binds with its receptor and could work through two different pathways: (i) it inhibits the expression of pro-inflammatory cytokines through blocking the TNF induced NFkB1 signaling pathway; and (ii) it initiates the expression of interferon-stimulating genes (ISGs) for antiviral defense program through activating the IFN-α induced Jak-STAT signaling pathway.ConclusionThis comprehensive study identified the pathways associated with cytokine storm in SARS-CoV-2 infection. The proposed underlying mechanism of Vitamin D could be promising in suppressing the cytokine storm and inducing a robust antiviral response in severe COVID-19 patients. The finding in this study urgently needs further experimental validations for the suitability of Vitamin D in combination with IFN-α to control severe COVID-19.
Highlights
The emergence and rapid spread of a highly pathogenic new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), created tremendous health, economic, and social crises worldwide
Our study indicates that the high expression of IRF9 in the SARS-CoV-2 infected cells could be involved in the formation of transcription factor ISGF3, which subsequently increases the expression of interferon-stimulated genes (ISGs)
The association of “host response signature network” with “cytokines and inflammatory response”, “non-genomic action of vitamin D”, “the human immune response to tuberculosis”, and “lung fibrosis” indicates that it plays an essential role in COVID-19 pathogenesis
Summary
The emergence and rapid spread of a highly pathogenic new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), created tremendous health, economic, and social crises worldwide. SARS-CoV-2 infects the cells of the lower respiratory tract and causes severe respiratory disease in humans, named coronavirus disease of 2019 (COVID-19). In late 2019, SARS-CoV-2 was reported in patients with severe pneumonia in Wuhan city of Hubei province, China. As of October 5, 2020, the number of SARS-CoV-2 infected people were 35,645,015; and among them, 1,044,898 cases of death and 26,791,820 cases of recovered were reported (https://www.worldometers.info/ coronavirus/). SARS-CoV-2 causes ongoing pandemic coronavirus disease of 2019 (COVID-19), infects the cells of the lower respiratory tract that leads to a cytokine storm in a significant number of patients resulting in severe pneumonia, shortness of breathing, respiratory and organ failure. Bioinformatics and systems biology approaches were used to understand SARS-CoV-2 induced cytokine pathways and the potential mechanism of Vitamin D in suppressing cytokine storm and enhancing antiviral response
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