SARS-CoV-2 infection has been shown to reduce the expression of vitamin D pathway components

A recent computational study from India included the unregulated pathway of vitamin D in the pathobiology of 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 at bioRxiv* pretprint server.

A major public health disaster due to coronavirus disease (COVID-19), a life-threatening disease caused by SARS-CoV-2, has launched a global research community in deciphering the underlying mechanisms and cellular pathways responsible for symptom diversity, severity, and disease progression , as well as recovery or death.

Vitamin D is a steroid hormone with multiple cellular functions; although the defective vitamin D pathway is associated with the pathobiology of SARS-CoV-2, the status of vitamin D-modulated genes in the lung cells of infected patients remains undetermined.

In short, the cellular effects of vitamin D derive from its non-genomic / cytoplasmic effects, but also its genomic / nuclear effects. Consequently, a myriad of receptors, enzymes, and factors affect how it modulates inflammation and feedback loops.

That is why the researchers, led by others. Bijesh George of the Rajiv Gandhi Center for Biotechnology (Trivandrum) and the Manipal Academy of Higher Education in India conducted a study to assess the exact status of the vitamin D pathway in SARS-CoV-2 -infected patients using public transcriptome datasets and rigorous computer approaches.

Cell lines, transcriptome approaches and network analysis

The researchers initially estimated the expression levels of the underlying components of the vitamin D pathway in different models of viral infection using the Signaling Pathways (SPPD) datasets – a set of transcriptional datasets biocuted by the Nuclear Receptor Signal Organization (NURSA).

The lung cells of patients with COVID-19 were then analyzed to evaluate vitamin D nucleus pathway molecules in three separate transcriptomate data sets based on sequencing of bronchoalveolar lavage fluid (BALF) RNA cells, but also in human lung cells A549, Calu3, and NHBE. SARS-CoV-2.

Finally, network analysis of different sets of genes was performed using the Network Analyst 3.0 tool. Moreover, functional enrichment analysis was done using Reactome, a freely available online database with intuitive bioinformatics tools.

Decreased expression of the vitamin D component

In summary, the results of this study support the notion of an alleged 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 of patients infected with the virus.

Expression of genes regulated by vitamin D in patients with COVID19.  a) The number of genes that overlap with vitamin D-regulated genes and the three SARS-COV-2 data sets are indicated.  b) 43 genes common to 3 sets of SARS-COV-2 data were identified and regulated by vitamin D, c) The bar chart shows a summary of the enrichment analysis in SARS-COV-2 from Metascape.  d) The bar diagram shows a summary of the functional enrichment analysis from Metascape.  e) The expression status of these 43 genes in patient data with SARS-COV-2 is plotted as a heat map.  f) A network analysis of 12 genes found to be regulated in all three patient data sets, and regulated by vitamin D, was also provided. Analysis of functional enrichment of 12 genes using Reactome identified “Pre-replicative complex activation” as the primary enrichment (rank 1, hit 9/32 pavlue 3.5e-11), Network analysis of 12 genes regulated in all three SARS-COV-2 patient transcript data sets.  Genes that are functionally linked to the immune system have been found (rank 57, 131/1140 pvalue 1.31e-21).

Expression of genes regulated by vitamin D in patients with COVID19. a) The number of genes that overlap with vitamin D-regulated genes and the three SARS-COV-2 data sets are indicated. b) 43 genes common to 3 sets of SARS-COV-2 data were identified and regulated by vitamin D, c) The bar chart shows a summary of the enrichment analysis in SARS-COV-2 from Metascape. d) The bar diagram shows a summary of the functional enrichment analysis from Metascape. e) The expression status of these 43 genes in patient data with SARS-COV-2 is plotted as a heat map. f) A network analysis of 12 genes found to be regulated in all three patient data sets, and regulated by vitamin D, was also provided. Analysis of functional enrichment of 12 genes using Reactome identified “Pre-replicative complex activation” as the primary enrichment (rank 1, hit 9/32 pavlue 3.5e-11), Network analysis of 12 genes regulated in all three SARS-COV-2 patient transcript data sets. Genes that are functionally linked to the immune system have been found (rank 57, 131/1140 pvalue 1.31e-21).

Furthermore, by identifying 107 differentially expressed and mostly down-regulated vitamin D-modulated genes in transcriptom datasets from patient cells, the role of direct and indirect mechanisms of gene expression by unregulated vitamin D was determined.

Detailed network analysis of such differentially expressed genes has revealed immune system pathways, NF-κB / cytokine signaling, and cell cycle regulation as major predictive events that may be affected in the cells of such patients.

Another new observation is the regulation of PAK1 expression (but not other families of AKT kinases for survival) in the same sets of SARS-CoV-2 samples with reduced expression of vitamin D pathway components, suggesting a potential correlation between the two phenomena, ”the authors say. studies.

A step towards experimental validation

All said, it is clear that this study provides important insights into the potentially causal relationship between the compromised pathway of vitamin D in many layers with SARS-CoV-2 infections in patients, resulting in dysregulation of pathways downstream to vitamin D.

This dysregulation is characterized by both down-regulation and under-regulation of vitamin D cellular genes, which includes molecules involved in the proinflammatory Th1 response and immune regulation.

These preliminary results now set the stage for the experimental validation of observations and postulates performed by computer approaches, ”the study authors conclude based on the results of their study.

In any case, this research sets the stage for larger studies that will confirm whether the compromised pathway of vitamin D can indeed affect lung cell sensitivity to SARS-CoV-2 and shed light on its exact role in the protein manifestations of COVID-19.

* Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered definitive, guide clinical practice / health-related behavior, or treat it as established information.

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