A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection

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.

“Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis”

“…Researchers have gone on to correlate the historical influenza pandemic of 1918–1919 to VDD [ 24 ]. By suppressing delayed dendritic cell activation and driving the ‘T’ cell response towards an anti-inflammatory (Th2/T-reg) domain rather than pro-inflammatory (Th1/Th17) one, vitamin may be instrumental for curtailing maladaptive cytokine storm seen with COVID-19, as seen in vitro studies [ 25 , 26 ].…”

Mild COVID-19 manifestation in multiple risk factor patient on methotrexate, who had been treated with UVB phototherapy and had sufficient plasma 25-OH-vitamin D3 level

“…Protective vitamin D3 mechanisms in COVID-19 patients are presumed to be multiple, including potent immunomodulatory activity, antiviral peptide induction, enhancement of physical barrier integrity and even direct interference with viral replication [13][14][15]47 . Vitamin D-mediated suppression of excessive T helper cell type 1 (Th1) response and proinflammatory cytokine hypersecretion is considered as one of the most important effect that reduces the likelihood of cytokine storm development, major pathogenic event concerning severe COVID-19 manifestation 14,15,[47][48][49] . Promoting induction of the T regulatory cells (Tregs), vitamin D may further enhance these immunomodulatory and anti-inflammatory effects 15 .…”

Empfehlung zu Vitamin D im Rahmen der COVID-19-Pandemie für Geriater*Innen und Hausärzt*Innen

“…Dazu kommen basiswissenschaftliche Studien , die zeigen, dass Vitamin D den COVID-19-induzierten Zytokinsturm zu unterdrücken scheint [ 14 , 15 ], als mögliche Erklärung, warum in verschiedenen Kohortenstudien ein höherer Vitamin-D-Blutspiegel mit einem geringeren Schweregrad der COVID-19-Erkrankung korreliert [ 8 – 12 ]. Bekannt ist, dass Vitamin D eine Rolle in der angeborenen und akuten Immunantwort spielt [ 16 ].…”