{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T15:54:30Z","timestamp":1777996470629,"version":"3.51.4"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T00:00:00Z","timestamp":1607472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>SARS-CoV-2 causes ongoing pandemic coronavirus\u00a0disease 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This 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 (<jats:italic>SiHgrn<\/jats:italic>). Analysis of <jats:italic>SiHgrn<\/jats:italic> identified a sub-network \u201c<jats:italic>Cluster 1<\/jats:italic>\u201d with the highest MCODE score, 31 up-regulated genes, and predominantly associated immune and inflammatory response. Interestingly, the iRegulone tool identified that \u201c<jats:italic>Cluster 1<\/jats:italic>\u201d is under the regulation of transcription factors STAT1, STAT2, STAT3, POU2F2, and NFkB1, collectively referred to as \u201c<jats:italic>host response signature network<\/jats:italic>\u201d. Functional enrichment analysis with NDEx revealed that the \u201c<jats:italic>host response signature network<\/jats:italic>\u201d is predominantly associated with critical pathways, including \u201ccytokines and inflammatory response\u201d, \u201cnon-genomic action of Vitamin D\u201d, \u201cthe human immune response to tuberculosis\u201d, and \u201clung fibrosis\u201d. 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-\u03b1 induced Jak-STAT signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This 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-\u03b1 to control severe COVID-19.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.590459","type":"journal-article","created":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T09:39:54Z","timestamp":1607506794000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":56,"title":["A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection"],"prefix":"10.3389","volume":"11","author":[{"given":"Firoz","family":"Ahmed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000000722","article-title":"Identification of a novel coronavirus causing severe 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