A recent computational study from India implicated a dysregulated vitamin D pathway in the pathobiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection – and opened the door for experimental validation of these observations. The paper is currently available on the bioRxiv* preprint server.
A major public health disaster due to the coronavirus disease (COVID-19), a life-threatening disease caused by SARS-CoV-2, has mobilized the global research community in deciphering fundamental mechanisms and cellular pathways responsible for the variety of symptoms . disease severity and progression, as well as recovery or death.
Vitamin D is a steroid hormone with many cell functions; Although 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.
In short, the cellular effects of vitamin D stem from its non-genomic / cytoplasmic effects, as well as its genomic / nuclear effects. As a result, a host of receptors, enzymes and factors are involved in the way it modulates inflammation and feedback loops.
This is why the researchers, led by Dr. Bijesh George of the Rajiv Gandhi Center for Biotechnology (Trivandrum) and Manipal Academy of Higher Education in India, conducted a study to determine the exact status of the vitamin D pathway in SARS CoV-2. infected patients using publicly available transcriptomic datasets and stringent computational approaches.
Cell lines, transcriptomic approaches and network analysis
The researchers initially assessed the expression levels of core components of the vitamin D pathway in various models of viral infection using the Signaling Pathways Project Datasets (SPPD) – a collection of transcriptomic datasets biocured by the Nuclear Receptor Signaling Atlas (NURSA Organization.
Then, the lung cells of COVID-19 patients were analyzed to evaluate core molecules of the vitamin D pathway in three separate RNA sequencing-based transcriptomic datasets of bronchoalveolar lavage fluid (BALF) cells, as well as in A549, Calu3 and NHBE human lung cells. . rules that express SARS-CoV-2.
Finally, the network analysis of different sets of genes was performed using the Network Analyst 3.0 tool. In addition, functional enrichment analysis was performed with Reactome, a freely accessible online pathway database with intuitive bioinformatics tools.
Decreased expression of components of the vitamin D pathway
In conclusion, the results of this study support the idea of a putative association between SARS-CoV-2 infection and decreased expression of various components of the vitamin D pathway. More specifically, there was a decrease in vitamin D and retinoid X receptors, as well as CYP27A1 (belonging to the cytochrome P450 gene family) in BALF cells from patients infected with the virus.
Expression of Vitamin D Regulated Genes in COVID19 Patients. a) The number of genes found overlaps with vitamin D regulated genes and three SARS-COV-2 datasets are shown. b) 43 genes were identified which are common to 3 SARS-COV-2 datasets and also regulated by vitamin D, c) Bar graph shows the summary of enrichment analysis in SARS-COV-2 from Metascape. d) Bar graph shows the summary of functional enrichment analysis in Metascape. e) The expression status of these 43 genes in SARS-COV-2 patient data is plotted as a heat map. f) Network analysis of 12 genes up-regulated in all three patient datasets and also regulated by vitamin D. 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 functionally related to the immune system (rank 57, 131/1140 p-value 1.31e-21) are noted.
In addition, the role of direct and indirect mechanisms of gene expression by the disrupted vitamin D has been established by identifying 10 7 differentially expressed and predominantly down-regulated genes modulated by vitamin D in transcriptomic patient cell data sets.
A detailed network analysis of such differentially expressed genes revealed immune system pathways, NF-kB / cytokine signaling, and cell cycle regulation as major predictive events that can be affected in the cells of such patients.
Another new noteworthy observation is the upregulation of PAK1 expression (but not another family of AKT survival kinases) in the same SARS-CoV-2 sample sets with reduced expression of vitamin D pathway components, suggesting a possible correlative suggests relationship between these two phenomena, “say the study authors.
A step towards experimental validation
All said, it is clear how this study provides important insights into a possible causal relationship between a compromised multilayer vitamin D pathway with SARS-CoV-2 infections in patients, resulting in disruption of the pathways downstream to vitamin D.
This dysregulation is characterized by both down and up regulation of vitamin D cellular genes, which means molecules involved in pro-inflammatory Th1 response and immune regulation.
These preliminary results now form the basis for experimental validation of the observations and postulations made using computational approaches, ”conclude the study authors based on the results of their study.
In any case, this study paves the way for larger studies that will confirm whether a compromised vitamin D pathway can indeed affect lung cells’ susceptibility to SARS-CoV-2, and clarify its exact role in the protein manifestations of COVID. . -19.
*Important announcement
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, serve clinical practice / health-related behavior, or be treated as established information.