A recent computational study in India involved a deregulated vitamin D pathway in the pathobiology of coronary virus severe acute respiratory syndrome infection (SARS-CoV-2) and opened the door to experimental validation of these observations. . The document is currently available at bioRxiv* prepress server.
A major public health disaster due to coronavirus disease (COVID-19), which is a life-threatening disease caused by SARS-CoV-2, mobilized the global research community to decipher fundamental mechanisms and cellular pathways responsible for the variety of symptoms, severity, and progression of the disease, as well as recovery or death.
Vitamin D is a steroid hormone with multiple cellular functions; although a defective vitamin D pathway has been linked to SARS-CoV-2 pathobiology, the status of vitamin D-modulated genes in the lung cells of infected patients remains undetermined.
In summary, the cellular effects of vitamin D are derived from its non-genomic / cytoplasmic effects, but also from its genomic / nuclear effects. Consequently, a myriad of receptors, enzymes, and factors are involved in how it modulates inflammation and feedback loops.
That is why researchers, led by Dr. Bijesh George, of the Rajiv Gandhi Biotechnology Center (Trivandrum) and the Manipal Academy of Higher Education of India, conducted a study to assess the exact status of the vitamin D pathway in SARS-CoV -2 -Infected patients using public transcriptomic data sets and strict computational approaches.
Cell lines, transcriptomic approaches, and network analysis
The researchers initially assessed the expression levels of the basic components of the vitamin D pathway in different models of viral infection using data sets from the Signaling Pathways (SPPD) project, a set of biocured transcriptomic data sets. by the organization NURSA (Atlas of signaling of the nuclear receiver).
Subsequently, the lung cells of patients with COVID-19 were analyzed to evaluate the basic molecules of the vitamin D pathway in three sets of transcriptomic data based on RNA sequencing separated from bronchoalveolar lavage fluid cells. (BALF), but also in human lung cells A549, Calu3 and NHBE. lines expressing SARS-CoV-2.
Finally, the network analysis of several gene sets has been performed using the Network Analyst 3.0 tool. In addition, functional enrichment analysis has been done using Reactome, a database of open-access online pathways with intuitive bioinformatics tools.
Reduced expression of vitamin D pathway components.
In summary, the results of this study support the notion of an alleged association between SARS-CoV-2 infection and the 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 the cytochrome P450 family of genes) in BALF cells of patients infected with the virus.
Expression of genes regulated by vitamin D in COVID19 patients. a) The number of genes found superimposed with genes regulated by vitamin D and three sets of SARS-VOC-2 data are denoted. b) 43 genes were identified that are common for 3 SARS-VOC-2 data sets and also regulated by vitamin D, c) The bar chart shows the summary of SARS-VOC-enrichment analysis 2 of Metascape. d) The bar chart shows the summary of the functional enrichment analysis from Metascape. e) The expression state of these 43 genes in the SARS-VOC-2 patient data is represented as a heat map. f) A network analysis of 12 genes found regulated in all three patients and which are also regulated by vitamin D is performed. The functional enrichment analysis of 12 genes using Reactome identified “Activation of the pre-replicative complex” as to primary enrichment (range 1, hits 9/32 pavlue 3.5e-11), network analysis of 12 down-regulated genes in the three SARS-VOC-2 patient transcriptome data sets. Genes functionally related to the immune system are found (range 57, 131/1140 value 1.31e-21).
In addition, by identifying 107 differentially expressed and mainly down-regulated genes modulated by vitamin D in transcriptomic data sets of patient cells, the role of direct and indirect mechanisms of gene expression has been established. for deregulated vitamin D.
A detailed network analysis of these differentially expressed genes revealed immune system pathways, NF-kB / cytokine signaling, and cell cycle regulation as major predictive events that may be affected in human cells. these patients.
Another notable new observation is the superior regulation of PAK1 expression (but not from another family of surviving AKT kinases) in the same SARS-CoV-2 sample sets with reduced expression of vitamin pathway components. D, which suggests a potential correlative relationship between these two phenomena, ”say the study’s authors.
A step towards experimental validation
That said, it is clear how this study provides an important insight into a potentially causal association between a compromised multilayer vitamin D pathway with SARS-CoV-2 infections in patients, resulting in a deregulation of the downstream pathways of the vitamin D.
This deregulation is characterized by both downward and upward regulation of cellular genes of vitamin D, which involves molecules involved in the proinflammatory response Th1 and immune regulation.
These preliminary results now set the stage for the experimental validation of observations and postulates made using computational approaches, ”the study authors conclude from the results of their study.
In any case, the stage is based on this research effort for broader studies that confirm whether a compromised vitamin D pathway may in fact 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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