COVID-19 Research: SARS-CoV-2 Dysregulates Vitamin D Pathway In Infected COVID-19 Patients

COVID-19 Research: Indian scientists from the Rajiv Gandhi Centre for Biotechnology, Trivandrum, Kerala-INDIA along with researchers from Rutgers New Jersey Medical School-USA and Virginia Commonwealth University Medical Center-USA have in a recent computational study implicated a dysregulated vitamin D pathway in the pathobiology of the infection with the SARS-CoV-2 coronavirus and opened the door for experimental validation of these observations.


 
Though a defective vitamin D pathway has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D pathway and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown.
 
In order to understand the significance of the vitamin D pathway in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes modulated by vitamin D were identified in transcriptomic datasets from patient’s cells.
 
Detailed analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D pathway in SARS-CoV-2-infected cells. Network analysis of differentially expressed vitamin D modulated genes identified pathways in the immune system, NF-kB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients.
 
The study findings provided computational evidence to implicate a dysregulated vitamin D pathway in the pathobiology of SARS-CoV-2 infection.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.21.423733v2
 
The vitamin D is a steroid hormone with manifold cellular functions; albeit a defective vitamin D pathway has been linked to SARS-CoV-2 pathobiology, the status of vitamin D-modulated genes in lung cells of infected patients remains undetermined.
 
Briefly cellular effects of vitamin D stem from its nongenomic/cytoplasmic effects, but also its genomic/nuclear effects. Consequently, a myriad of receptors, enzymes and factors are implicated in how it modulates inflammation and feedback loops.
 
Hence the reason as to why the researchers, led by Dr Bijesh George from the Rajiv Gandhi Centre for Biotechnology (Trivandrum) and Manipal Academy of Higher Education in India, conducted the research to appraise the exact status of the vitamin D pathway in SARS-CoV-2-infected patients by using public transcriptomic datasets and stringent computational approaches.
 
The study team initially assessed the expression levels of core components of the vitamin D pathway in different models of viral infection by utilizing the Signaling Pathways Project Datasets (SPPD) ie an assemblage of transcriptomic datasets biocurated by the Nuclear Receptor Signaling Atlas ( NURSA) Organization.
 
They then analyzed the lung cells of COVID-19 patients to evaluate core molecules of the vitamin D pathway in three separate RNA sequencing-based transcriptomic datasets of bronchoalveolar lavage fluid (BALF) cells, but also in A549, Calu3 and NHBE human lung cell lines expressing SARS-CoV-2.
 
Lastly, the network analysis of various sets of genes has been performed with the use of the Network Analyst 3.0 tool. Moreover, functional enrichment analysis has been done by using Reactome, a freely accessible online pathway database with intuitive bioinformatics tools.


Expression of Vitamin D regulated genes in COVID19 patients. a) Number of genes found overlapped with Vitamin D regulated genes and three SARS-COV-2 datasets are denoted. b) 43 genes were identified which are common for 3 SARS-COV-2 datasets and also regulated by Vitamin D, c) Bar diagram shows the summary of enrichment analysis in SARS-COV-2 from Metascape. d) Bar diagram shows the summary of functional enrichment analysis in from Metascape. e) The expression status of these 43 genes in SARS-COV-2 patient data is plotted as heat map. f) Network analysis of 12 genes found up-regulated in all three patient dataset and also regulated by Vitamin D is given. The functional enrichment analysis of 12 genes using Reactome identified “Activation of the pre-replicative complex” as primary enrichment (rank 1, hits 9/32 pavlue 3.5e-11), Network analysis of 12 genes downregulated in all three SARS-COV-2 patient transcriptome datasets. Genes are found functionally related to immune system (rank 57, 131/1140 p-value 1.31e-21) are remarked.

The study findings support the notion of a purported association between SARS-CoV-2 infection and reduced expression of different components of the vitamin D pathway. More specifically, there was a reduction of vitamin D and retinoid X receptors, as well as CYP27A1 (belonging to cytochrome P450 gene family) in BALF cells of patients infected with the virus.
 
In addition by identifying 107 differentially expressed and chiefly down-regulated genes modulated by vitamin D in transcriptomic datasets from patients’ cells, the role of direct and indirect mechanisms of gene expression by the dysregulated vitamin D has been established.
 
A further detailed network analysis of such differentially expressed genes revealed immune system pathways, NF-kB/cytokine signaling, and cell cycle regulation as prime predictive events that may be affected in the cells of such patients.
 
Interestingly another novel notable observation is the upregulation of PAK1 expression (but not another family of survival AKT kinases) in the same SARS-CoV-2 sample sets with a reduced expression of vitamin D pathway components, suggesting a potential correlative relationship between these two phenomena.
 
The study findings provide important insights about a potentially causal association between a compromised vitamin D pathway on many layers with SARS-CoV-2 infections in patients, resulting in a dysregulation of pathways downstream to vitamin D.
 
Significantly this dysregulation is characterized by both down-regulation and up-regulation of vitamin D cellular genes, which entails molecules that are involved in proinflammatory Th1 response and immune regulation.
 
The study findings although preliminary now set the stage for experimental validation of the observations and postulations made using computational approaches.
 
The stage is set by this research endeavor for larger studies that will confirm whether a compromised vitamin D pathway can indeed influence the susceptibility of lung cells to SARS-CoV-2, and elucidate its exact role in the protean manifestations of COVID-19.
 
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