key: cord-0755579-bwvtqeda authors: Ahmed, Sara M.; Nasr, Mohamed A.; Elshenawy, Shimaa E.; Hussein, Alaa E.; El-Betar, Ahmed H.; Mohamed, Rania Hassan; El-Badri, Nagwa title: BCG vaccination and the risk of COVID 19: A possible correlation date: 2021-10-28 journal: Virology DOI: 10.1016/j.virol.2021.10.003 sha: 57b85622f44c1f828372ffbd9a437349e15ffa12 doc_id: 755579 cord_uid: bwvtqeda Bacillus Calmette–Guérin (BCG) vaccine is currently used to prevent tuberculosis infection. The vaccine was found to enhance resistance to certain types of infection including positive sense RNA viruses. The current COVID-19 pandemic is caused by positive sense RNA, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A higher mortality rate of COVID-19 patients was reported in countries where BCG vaccination is not routinely administered, when compared to the vaccinated ones. We hypothesized that BCG vaccine may control SARS-CoV2 infection via modulating the monocyte immune response. We analyzed GSE104149 dataset to investigate whether human monocytes of BCG-vaccinated individuals acquire resistance to SARS-CoV-2 infection. Differentially expressed genes obtained from the dataset were used to determine enriched pathways, biological processes, and molecular functions for monocytes post BCG vaccination. Our data show that BCG vaccine promotes a more effective immune response of monocytes against SARS-CoV2, but probably not sufficient to prevent the infection. . Other studies reported that BCG vaccine 60 ameliorated the severity of positive sense RNA viruses, such as mengovirus and yellow 61 fever virus [3, 5] . The mechanism underlying this effect was attributed to genetic or 62 epigenetic modulation of the innate immune system in a process known as trained 63 immunity [3, 6] . Trained immunity is initiated through the response of innate immune 64 cells to microbial antigen that causes epigenetic and metabolic changes, that upon re-65 infection, a more significant response to the antigen occurs [7, 8] . 66 The current COVID-19 pandemic is caused by the positive sense RNA virus, severe 67 acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological studies 68 reported decreased mortality rate of BCG vaccinated individuals who were infected 69 with SARS-CoV-2 [5, [9] [10] [11] [12] [13] [14] . It was thus proposed that BCG vaccine may be effective 79 Epidemiological studies have shown that BCG vaccination significantly decreased 80 child mortality in Europe in the 1920's. Randomized controlled trials showed that there 81 is a reduction in BCG-induced mortality in young infants by up to 50% [17, 18] . These 82 studies did not however distinguish between bacterial and viral infections, although it 83 is well documented that viral pathogens are the major cause of respiratory tract 84 infections in children [19] . BCG vaccine boosted the innate immune response upon re-85 stimulation with different infectious pathogens, in a process known as "trained 86 immunity" [20] . Despite the fact that the vaccine has been designed and used against reported an increase in the peripheral blood CD14 + CD16 + monocytes, which increased Our analysis generated gene expression profiles of about 26175 genes (including some 156 gene duplicates), which were then filtered by elimination of statistically non-significant 157 data (P-value > 0.05). The use of P-value instead of the adjusted P-value was based on 158 the fact that the sample size was too small for using the latter. This was supported by 159 obtaining the same adjusted value for all genes expression (value=1), which was not 160 sufficient for data filtering. Only 89 genes out of the 26175 were found to be statistically 161 significant and were used for downstream analysis, as shown in (Supplementary Table 162 1). 163 We then used Enrichr online enrichment analysis tool in search for the biological on these pathways that are relevant to viruses (Table 3) . 187 All of the 8 GO biological processes shared a set of 6 commonly enriched genes that 188 were obtained from our selected GEO dataset, while 7 processes shared a set of 7 189 common enriched genes. We further identified the PANTHER family of these genes in 190 addition to the biological processes in which each gene is involved (Table 4) . We compared the whole set of genes that were enriched for viral biological processes, Figures 1-3) . We 197 therefore report the fold change expression of these genes in addition to the rank of each 198 common biological process in (Table 5) . Using STRING tool v11.0, we were able to obtain protein-protein interaction network (Table. 246 2). The interferon-induced protein with tetratricopeptide repeats (IFIT) family is composed For its spectrum of antiviral activity, EIF2AK2 gene is suspected to be one of the genes 305 stimulated by BCG vaccine to boost the antiviral cellular innate immunity. As can be inferred, most of the common enriched genes are interferon-inducible genes 307 that have antiviral mechanisms except for the CXCL8 chemokine. All these genes, CoV2 are essential to confirm these findings. Hyperglycemia-induced reactive oxygen species increase 455 expression of the receptor for advanced glycation end products (RAGE) and RAGE 456 ligands Multiple intravenous infusions of bone marrow mesenchymal stem cells 458 reverse hyperglycemia in experimental type 2 diabetes rats. Biochemical and 459 biophysical research communications High glucose induces bone marrow-derived 461 mesenchymal stem cell senescence by upregulating autophagy The role of Toll-like receptor 10 in modulation of trained immunity GREIN: An Interactive Web Platform for Re-analyzing GEO RNA-seq 466 Enrichr: interactive and collaborative HTML5 gene list enrichment 468 analysis tool Enrichr: a comprehensive gene set enrichment analysis web 470 server 2016 update OLSVis: an animated, interactive visual 472 browser for bio-ontologies The Gene Ontology Resource: 20 years and still GOing strong PANTHER version 14: more genomes, a new PANTHER GO-slim and 482 improvements in enrichment analysis tools VennPainter: A Tool for the Comparison and Identification of Candidate 485 STRING v11: protein-protein association networks with increased 487 coverage, supporting functional discovery in genome-wide experimental datasets Diabetes mellitus type 2 reduces the viability, proliferation, and 490 angiogenic marker of adipose-derived stem cells cultured in low-glucose anti-oxidant-491 serum supplemented medium High levels of interleukin-8 in the blood and alveolar spaces 494 of patients with pneumonia and adult respiratory distress syndrome. Infection and 495 immunity Mesenchymal stem cell-based treatment for microvascular and 497 secondary complications of diabetes mellitus. Frontiers in endocrinology Influenza A virus-induced IFN-α/β and IL-18 synergistically enhance 502 IFN-γ gene expression in human T cells Influenza A and sendai viruses induce differential chemokine 505 gene expression and transcription factor activation in human macrophages Percutaneous injection of bone marrow mesenchymal stem cells 508 for ankle non-unions decreases complications in patients with diabetes Serum IFN-gamma-induced protein 10 (IP-10) as a biomarker for 511 severity of acute respiratory infection in healthy adults Are serum cytokines early predictors for the outcome of burn 513 patients with inhalation injuries who do not survive? Crit Care Essential involvement of interleukin-8 (IL-8) in acute inflammation Neutrophil chemotaxis caused by chronic obstructive pulmonary 517 disease alveolar macrophages: the role of CXCL8 and the receptors CXCR1/CXCR2. 518 Attracting Attention: Discovery of IL-8/CXCL8 and the 520 Birth of the Chemokine Field High levels of interleukin-8 in the blood and alveolar spaces 523 of patients with pneumonia and adult respiratory distress syndrome Elevated levels of NAP-1/interleukin-8 are present in the airspaces of 526 patients with the adult respiratory distress syndrome and are associated with 527 increased mortality The alveolar space is the site of intense inflammatory and profibrotic 529 reactions in the early phase of acute respiratory distress syndrome Advanced protein glycosylation in diabetes and aging Transcriptional profiling reveals intrinsic mRNA alterations in 534 multipotent mesenchymal stromal cells isolated from bone marrow of newly-535 diagnosed type 1 diabetes patients. Stem cell research & therapy IFIT1: A dual sensor and effector molecule that detects non-2'-O 539 methylated viral RNA and inhibits its translation Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-542 O-Ribose Methyltransferase Nsp16 of SARS-CoV-2. 2020 The antiaging gene klotho regulates proliferation and differentiation 544 of adipose-derived stem cells Green propolis extract promotes in vitro 546 proliferation, differentiation, and migration of bone marrow stromal cells Cell biology of aging Preadipocytes of type 2 diabetes subjects display an intrinsic 550 gene expression profile of decreased differentiation capacity. International journal of 551 obesity Diabetes impairs adipose tissue-derived stem cell function and 553 efficiency in promoting wound healing. Wound repair and regeneration Increased oxidative stress induced by rubus bioactive 556 compounds induce apoptotic cell death in human breast cancer cells. Oxidative 557 medicine and cellular longevity Importance of Sox2 in maintenance of cell proliferation and 559 multipotency of mesenchymal stem cells in low-density culture. Cell proliferation Similarities and differences between mesenchymal 562 stem/progenitor cells derived from various human tissues. World journal of stem cells Enhanced proliferation and differentiation of Oct4-and Sox2-565 overexpressing human adipose tissue mesenchymal stem cells. Experimental & 566 molecular medicine Inflammatory cytokines in type 2 diabetes mellitus as facilitators 568 of hypercoagulation and abnormal clot formation The antiviral activities of ISG15 Antiviral activity of innate immune protein 575 ISG15 The papain-like protease determines a virulence trait that varies 577 among members of the SARS-coronavirus species Selectivity in ISG15 and ubiquitin recognition by the SARS 580 coronavirus papain-like protease Protein interferon-stimulated gene 15 conjugation delays but does not 583 overcome coronavirus proliferation in a model of fulminant hepatitis Inhibition of papain-like protease PLpro blocks SARS-CoV-2 spread and 586 promotes anti-viral immunity IFITM-Family Proteins: The Cell's First Line of Antiviral Defense. 588 Annual review of virology Interferon-Induced Transmembrane Protein 1 Restricts Replication 590 of Viruses That Enter Cells via the Plasma Membrane Devipriya Nagarajan, Suma Mohan S, 595 Host transcriptome-guided drug repurposing for COVID-19 treatment: a meta-analysis 596 based approach SARS-CoV-2 launches a unique transcriptional signature from 598 in vitro, ex vivo, and in vivo systems Viperin: a multifunctional, interferon-inducible 600 protein that regulates virus replication A naturally occurring antiviral ribonucleotide encoded by the human 602 genome Viperin Targets Flavivirus Virulence by Inducing Assembly of 604 Noninfectious Capsid Particles A Kinome-Wide Small Interfering RNA Screen Identifies Proviral 606 and Antiviral Host Factors in Severe Acute Respiratory Syndrome Coronavirus 607 Antiviral Activity of Human OASL Protein Is Mediated by Enhancing 610 Signaling of the RIG-I RNA Sensor Oligoadenylate synthase-like (OASL) proteins: dual functions and 612 associations with diseases. Experimental & molecular medicine Early gene expression events in ferrets in response to SARS 615 coronavirus infection versus direct interferon-alpha2b stimulation There are several reports on the role of Bacillus Calmette-Guerin (BCG) vaccination in non-specific modulation of the immune responses against various types of infection including positive sense RNA viruses 2. The current COVID-19 pandemic is caused by positive sense RNA A higher mortality rate of COVID-19 patients was reported in countries where BCG vaccination is not routinely administered Human monocytes are critical during the immune response against SARS-CoV-2 We used bioinformatics tool to investigate whether human monocytes of BCG-vaccinated individuals acquire resistance to SARS-CoV-2 infection Our data show that BCG vaccine promotes a more effective immune response of monocytes against SARS-CoV2, but probably not sufficient to prevent the infection J o u r n a l P r e -p r o o f