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Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination.

ABSTRACT: Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB) and induces highly variable protection against pulmonary disease in different countries. We hypothesised that DNA methylation is one of the molecular mechanisms driving variability in BCG-induced immune responses. DNA methylation in peripheral blood mononuclear cells (PBMC) from BCG vaccinated infants was measured and comparisons made between low and high BCG-specific cytokine responders. We found 318 genes and 67 pathways with distinct patterns of DNA methylation, including immune pathways, e.g. for T cell activation, that are known to directly affect immune responses. We also highlight signalling pathways that could indirectly affect the BCG-induced immune response: potassium and calcium channel, muscarinic acetylcholine receptor, G Protein coupled receptor (GPCR), glutamate signalling and WNT pathways. This study suggests that in addition to immune pathways, cellular processes drive vaccine-induced immune responses. Our results highlight mechanisms that require consideration when designing new TB vaccines.

SUBMITTER: Hasso-Agopsowicz M

PROVIDER: S-EPMC6117309 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination.

Hasso-Agopsowicz Mateusz M Scriba Thomas J TJ Hanekom Willem A WA Dockrell Hazel M HM Smith Steven G SG

Scientific reports 20180830 1

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB) and induces highly variable protection against pulmonary disease in different countries. We hypothesised that DNA methylation is one of the molecular mechanisms driving variability in BCG-induced immune responses. DNA methylation in peripheral blood mononuclear cells (PBMC) from BCG vaccinated infants was measured and comparisons made between low and high BCG-specific cytokine responders. We found 318 genes and 67 ...[more]

PMID: 30166570

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Project description:In many countries where tuberculosis (TB) is endemic, the Bacillus Calmette-Guérin (BCG) vaccine is given as close to birth as possible to protect infants and children from severe forms of TB. However, BCG has variable efficacy and is not as effective against adult pulmonary TB. At present, most animal models used to study novel TB vaccine candidates rely on the use of adult animals. Human studies show that the infant immune system is different to that of an adult. Understanding how the phenotypic profile and functional ability of the immature host immune system compares to that of a mature adult, together with the subsequent BCG immune response, is critical to ensuring that new TB vaccines are tested in the most appropriate models. BCG-specific immune responses were detected in macaques vaccinated within a week of birth from six weeks after immunization indicating that neonatal macaques are able to generate a functional cellular response to the vaccine. However, the responses measured were significantly lower than those typically observed following BCG vaccination in adult rhesus macaques and infant profiles were skewed towards the activation and attraction of macrophages and monocytes and the synthesis in addition to release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. The frequency of specific immune cell populations changed significantly through the first three years of life as the infants developed into young adult macaques. Notably, the CD4:CD8 ratio significantly declined as the macaques aged due to a significant decrease in the proportion of CD4+ T-cells relative to a significant increase in CD8+ T-cells. Also, the frequency of both CD4+ and CD8+ T-cells expressing the memory marker CD95, and memory subset populations including effector memory, central memory and stem cell memory, increased significantly as animals matured. Infant macaques, vaccinated with BCG within a week of birth, possessed a significantly higher frequency of CD14+ classical monocytes and granulocytes which remained different throughout the first three years of life compared to unvaccinated age matched animals. These findings, along with the increase in monokines following vaccination in infants, may provide an insight into the mechanism by which vaccination with BCG is able to provide non-specific immunity against non-mycobacterial organisms.

Project description:IntroductionPrenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants.Material and methodsMaternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other's effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray.ResultsMaternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus -0.94 in scar-negative, p=0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation.ConclusionsMaternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile.

Dataset Information

Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination.

Publications

Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination.

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