Hidden in plain sight: The effects of BCG vaccination in COVID-19 pandemic

Abstract

To investigate the relationship between BCG vaccination and SARS-CoV-2 by bioinformatic approach. Two datasets for Sars-CoV-2 infection group and BCG-vaccinated group were downloaded. Differentially Expressed Genes were identified.Gene ontology and pathways were functionally enriched, and networking was constructed in NetworkAnalyst. Lastly, correlation between post-BCG vaccination and COVID-19 transcriptome signatures were established. A total of 161 DEGs (113 upregulated DEGs and 48 downregulated genes) were identified in the Sars-CoV-2 group. In the pathway enrichment analysis, cross-reference of upregulated KEGG pathways in Sars-CoV-2 with downregulated counterparts in the BCGvaccinated group, resulted in the intersection of 45 common pathways, accounting for 86.5% of SARS-CoV-2 upregulated pathways. Of these intersecting pathways, a vast majority were immune and inflammatory pathways with top significance in IL-17, TNF, NOD-like receptors, and NF-κB signaling pathways. Our data suggests BCG-vaccination may incur a protective role in COVID-19 patients until a targeted vaccine is developed. Supplementary Materials (https://drive.google.com/open?id=15Na738L282XNaQAJUh0cZf1WoG9jJfzJ)2|P a g e 4|P a g e Data pre-processing and differential expression analysis After background correction of raw expression data, mapped multiple probes to the same genes were summarized to gene levels by using the median. Genes were filtered out if variance percentile rank lower than the threshold (set at 15%) or low relative abundance (average expression signal) below 5%. To ensure similar expression distributions of each sample across the entire experiment, normalization by log2 transformation method was performed. The quality of the normalized dataset was checked with the box plot and density plot, and the Benjamini and Hochberg method was selected for the multiple testing correction. Using the Limma R package available on Bioconductor (http://bioconductor.org/packages/release/bioc/html/limma.html), differentially expressed genes (DEGs) were identified in the microarray dataset. Genes with false discovery rate (FDR) <0.05 and log2-fold change (FC) ≥1.0 were considered as significantly differentially expressed and subjected to further analysis. For the RNA seq data of BCG vaccine, gene expression signature was generated by comparing gene expression levels of the post-vaccination groups with the control group at day 0. Altered patterns of gene expression were defined through each experimental time (FC>1|P<0.05). To visually identify the similarities and differences between different cell line samples, principal component analysis (PCA) was plotted to project high-dimensional data into lower dimensions using linear transformation. Functional Enrichment AnalysisGene Ontology (GO) database for function annotation of genes was used to analyze the DEGs at the functional level in terms of biological processes, molecular function, and cellular component domains 34 . Pathway functional analysis was performed in the Kyoto Encyclopedia of Gen...

Vitamin D insufficiency as a potential culprit in critical COVID‐19 patients

“…26 The importance of vitamin D and immunity is echoed by the fact that Bacillus Calmette-Guérin (BCG) vaccination in COVID-19 patients appears to have a protective effect via the upregulation of the same pathways mentioned above. 24 Differences noted in subgroup analyses could be attributed to…”

“…Cathelicidins serve to disrupt the bacterial cell membranes, as well the enveloped viruses such as SARS‐CoV‐2, while defensins promote chemotaxis of inflammatory cells via increased capillary permeability 23 . Despite vitamin D promoting the expression of several inflammatory cytokines via T‐cell inactivation and interferon‐γ activation, 24 it simultaneously downregulates pro‐inflammatory markers interleukin‐6 and tumor necrosis factor‐α the two key cytokines involved with the development of the “cytokine storm” that precedes ARDS 25 . Given this understanding at the molecular level, one can reasonably imply that patients with vitamin D deficiency are at an increased risk of developing more severe manifestations of COVID‐19 and/or worse prognosis 26 .…”

“…Given this understanding at the molecular level, one can reasonably imply that patients with vitamin D deficiency are at an increased risk of developing more severe manifestations of COVID‐19 and/or worse prognosis 26 . The importance of vitamin D and immunity is echoed by the fact that Bacillus Calmette–Guérin (BCG) vaccination in COVID‐19 patients appears to have a protective effect via the upregulation of the same pathways mentioned above 24 …”

Association between presence of Bacillus Calmette–Guerin vaccine scar and coronavirus disease 2019

“…[25] In a molecular study, it was also shown that BCG vaccination is protective against SARS-CoV-2 by nonspecific ways. [8]…”

“…[3,6] Innate immune cells (monocytes, macrophages, natural killer cells) which are prepared by microbial PAMPs for a secondary exposure; play a role in trained immunity [3,7] and these cells increase the release of the proinflamatuarty cytokines (Interleukin-1β, tumor necrosis factor, and interleukin-6). [8]…”