Transcriptional signature of BCG vaccination
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156422 | GEO | 2021/12/06
REPOSITORIES: GEO
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Project description:The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.
2021-12-23 | GSE188586 | GEO
Project description:Tuberculosis (TB) is one of major causes of death worldwide. Bacillus Calmette-Guerin (BCG) is the only licensed TB vaccine and its inability to protect against adult pulmonary TB can be due to genetic differences among strains described since the 1940s. In this work, we compared the proteomic profile of the surface-associated proteins from M. bovis BCG Moreau, the Brazilian vaccine strain, and the BCG Pasteur reference strain. The methodology used was 2D-gel electrophoresis combined with mass spectrometry techniques (MALDI-TOF/TOF). We identified 115 proteins. Of these, 24 proteins showed differential expression between the two BCG strains. Furthermore, 27 proteins previously described as displaying moonlighting function were identified, 8 of these proteins showed variation in abundance comparing BCG Moreau to Pasteur and 2 of them presented two different domain hits.
2019-05-15 | PXD006141 | Pride
Project description:Bacille Calmette Guerin (BCG) is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) disease. However, BCG has limited efficacy, necessitating the development of better vaccines. Non-tuberculous mycobacteria (NTM), a distinct lineage from Mtb, are opportunistic pathogens present in the environment. TB endemic countries experience higher exposure to NTM, but previous studies have not elucidated the relationship between NTM exposure and BCG efficacy. Therefore, we developed a mouse model (BCG+NTM) that mimics human BCG vaccination at an early stage and continuous NTM exposure via the oral route, including during TB infection. Our results show that BCG+NTM mice had improved protection against pulmonary TB correlating with increased pulmonary influx of B-cells, higher titers of anti-Mtb IgA and IgG antibodies in serum and airways, compared to mice vaccinated with BCG alone. Notably, the lungs of BCG+NTM mice developed B-cell aggregates expressing markers of germinal center formation as determined by spatial transcriptomics. We conclude a direct correlation between NTM exposure and protection from TB, with B-cells playing a crucial role.
2022-10-23 | GSE203037 | GEO
Project description:A greater understanding of the relationships between a vaccine, the immune response it induces, and protection from disease would greatly facilitate vaccine development. Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis (TB) vaccine designed to enhance responses induced by Bacille Calmette-Guerin (BCG). Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A and peaks one week post-vaccination, however, the variability in response between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression following vaccination with MVA85A and understand how these are related to long-term immunogenicity. 24 volunteers were vaccinated with 10^8 pfu MVA85A. 12 volunteers were vaccinated intramuscularly and 12 intradermally. Volunteers were healthy and did not have HIV, HCV, HBV or latent or active tuberculosis. Blood for this study was taken on the day of vaccination, immediately prior to the vaccine being given (day 0), and 2 and 7 days post-vaccination. Volunteers with a prior BCG vaccination were vaccinated with 1x10^8 pfu MVA85A either intradermally (id) or intramuscularly (im). Blood was taken immediately prior to vaccination (day 0) and 2 and 7 days post-vaccination. PBMCs were separated and frozen down. PBMCs were then thawed and RNA was extracted directly for microarray analysis. Some arrays contain control samples: from volunteers, incubated with either media alone or antigen 85, MVA85A or MVA wild type. These samples were used separately.
2012-09-28 | E-GEOD-40719 | biostudies-arrayexpress
Project description:A greater understanding of the relationships between a vaccine, the immune response it induces, and protection from disease would greatly facilitate vaccine development. Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis (TB) vaccine designed to enhance responses induced by Bacille Calmette-Guerin (BCG). Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A and peaks one week post-vaccination, however, the variability in response between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression following vaccination with MVA85A and understand how these are related to long-term immunogenicity. 24 volunteers were vaccinated with 10^8 pfu MVA85A. 12 volunteers were vaccinated intramuscularly and 12 intradermally. Volunteers were healthy and did not have HIV, HCV, HBV or latent or active tuberculosis. Blood for this study was taken on the day of vaccination, immediately prior to the vaccine being given (day 0), and 2 and 7 days post-vaccination.
2012-09-28 | GSE40719 | GEO
Project description:Vaccination against tuberculosis by intradermal Bacillus Calmette-Guérin (BCG) injection saves many lives, supposedly by inducing adaptive immune memory in lymphocytes. Epidemiologically, BCG vaccination is also associated with reduced childhood mortality unrelated to TB, which is attributed to innate immune memory, also termed trained immunity. We recently demonstrated improved protection against tuberculosis infection in highly susceptible rhesus macaques by mucosal BCG vaccination, correlating with a unique local but no peripheral immune profile. Here, we investigated local and peripheral innate immune function after intradermal versus mucosal vaccination with M. bovis BCG or the live attenuated, M. tuberculosis-derived candidate, MTBVAC. The results demonstrate an augmented frequency of trained immunity in monocytes after respiratory mucosal administration of live attenuated mycobacterial vaccines compared to intradermal immunization, with MTBVAC being equally potent as BCG. These results provide further support to strategies for improving TB vaccination and, more broadly, modulating innate immunity via mucosal surfaces.
2021-01-27 | GSE159046 | GEO
Project description:The reason for the largely variable protective effect against TB of the vaccine Bacille Calmette-Guerin (BCG) is not understood. In this study, we investigated whether epigenetic mechanisms are involved in the response of immune cells to the BCG vaccine. We isolated peripheral blood mononuclear cells (PBMCs) from BCG-vaccinated subjects and performed global DNA methylation analysis in combination with functional assays representative of innate immunity against Mycobacterium tuberculosis infection. Enhanced containment of replication was observed in monocyte-derived macrophages from a sub-group of BCG-vaccinated individuals (identified as ‘responders’). A stable and robust differential DNA methylation pattern in response to BCG could be observed in PBMCs isolated from the responders but not from the non-responders. Gene ontology analysis revealed that promoters with altered DNA methylation pattern were strongly enriched among genes belonging to immune pathways in responders, however no enrichments could be observed in the non-responders. Our findings suggest that BCG-induced epigenetic reprogramming of immune cell function can enhance anti-mycobacterial immunity. Understanding why BCG induces this responses in responders but not in nnon-responders could provide clues to improvement of TB vaccine efficacy.
2017-09-27 | GSE104287 | GEO
Project description:Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a prospective case–control analysis to identify the drivers of immune activation in infants and found cytomegalovirus (CMV) stimulated IFN-γ-expressing cells to be associated with CD8+ T cell activation (Spearman’s rho r = 0.241, p <0.0001). Among 49 infants who developed incident TB disease and 129 matched controls who remained healthy we found that CMV and Epstein–Barr virus (EBV) specific IFN-γ responses were associated with increased risk of developing TB (Fisher’s Exact Test, p=0.049, OR 2.14, 95% CI 1.03-4.47), and associated with a shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.012). T cell activation and CMV are associated with lower mycobacterial antigen-specific immune responses following immunization with Bacille Calmette-Guerin (BCG) and MVA85A, suggesting that increased susceptibility to TB in infants with virus infection may, in part, be due to poor responsiveness to vaccination. Understanding of the causes and impact of T cell activation could transform strategies used to protect against TB disease.
2018-12-05 | GSE98550 | GEO
Project description:Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease that affects one-third of the world’s population. The sole extant vaccine for tuberculosis is the live attenuated Mycobacterium bovis bacille Calmette-Guerin (BCG). We examined 13 representative BCG strains from around the world to ascertain their ability to express DosR-regulated dormancy antigens. These are known to be recognized by T-cells of M. tuberculosis infected individuals, especially those harboring latent infections. Differences in expression of these antigens could be valuable for use as diagnostic markers to distinguish BCG vaccination from latent tuberculosis. We determined that all BCG strains were defective for induction of two dormancy genes, narK2 (Rv1737c) and narX (Rv1736c). NarK2 is known to be necessary for nitrate respiration during anaerobic dormancy. Analysis of the narK2/X promoter region revealed a base substitution mutation in all tested BCG strains and M. bovis in comparison to the M. tuberculosis sequence. We also show that nitrate reduction by BCG strains during dormancy was greatly reduced compared to M. tuberculosis and varied between tested strains. Several dormancy regulon transcriptional differences were also identified among the strains, as well as variation in their growth and survival. These findings demonstrate defects in DosR regulon expression during dormancy and phenotypic variation between commonly used BCG vaccine strains. 12 different BCG strains were examined as well as M. tuberculosis H37Rv and M. bovis. Two arrays per strain were analyzed, one with the addition of nitric oxide and the other utilizing hypoxia treatment, both conditions shown to induce expression of the dormancy regulon. The reference sample for each array was log phase M. tuberculosis H37Rv.
2008-05-03 | E-GEOD-11315 | biostudies-arrayexpress
Project description:Bacille Calmette Guerin (BCG) is the most widely administered vaccine in the world yet its mechanism of action remains unclear. In this study, we have used samples from a human mycobacterial challenge study in which previously BCG-vaccinated or BCG-naïve UK adults were challenged intradermally with a standard dose of BCG vaccine. BCG remaining at the site of vaccination was quantified by polymerase chain reaction from a skin biopsy sample taken two weeks post-challenge and was used as a measure of BCG growth and functional anti-mycobacterial immunity. Using gene expression microarrays and flow cytometric analysis of intracellular cytokine production, we show that the magnitude of the immune response is greater in previously vaccinated volunteers and that this correlates with reduced mycobacterial growth but increased scarring at the vaccination site. In particular the IFNγ and IL-17 pathways are strongly induced in previously vaccinated volunteers and correlate with reduced mycobacterial growth in this population. This study supports the use of BCG challenge as a tool for evaluating vaccine efficacy and identifying mechanisms of anti-mycobacterial immunity
2014-12-01 | GSE58636 | GEO