Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination

Abstract

The antituberculosis vaccine Bacillus Calmette–Guérin (BCG) induces nonspecific protection against heterologous infections, at least partly through induction of innate immune memory (trained immunity). The amplitude of the response to BCG is variable, but the factors that influence this response are poorly understood. Metabolites, either released by cells or absorbed from the gut, are known to influence immune responses, but whether they impact BCG responses is not known. We vaccinated 325 healthy individuals with BCG, and collected blood before, 2 weeks and 3 months after vaccination, to assess the influence of circulating metabolites on the immune responses induced by BCG. Circulating metabolite concentrations after BCG vaccination were found to have a more pronounced impact on trained immunity responses, such as the increase in IL-1β and TNF-α production upon Staphylococcus aureus stimulation, than on specific adaptive immune memory, assessed as IFN-γ production in response to Mycobacterium tuberculosis. Circulating metabolites at baseline were able to predict trained immunity responses at 3 months after vaccination and enrichment analysis based on the metabolites positively associated with trained immunity revealed enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both of which were previously found to be important for trained immunity. Several new metabolic pathways that influence trained immunity were identified, among which taurine metabolism associated with BCG-induced trained immunity, a finding validated in functional experiments. In conclusion, circulating metabolites are important factors influencing BCG-induced trained immunity in humans. Modulation of metabolic pathways may be a novel strategy to improve vaccine and trained immunity responses.

Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker

“…The strong and positive relationship between taurine and an immunized antibody level reinforces the suggestion that vaccination can establish a reciprocal regulatory relationship between taurine and neutralizing antibodies. The observations in this study are somewhat in concert with the results of previous research in relation to BCG-induced protective effects as with taurine ( 42 ). However, this is the first study implicating a potential role for taurine in response to SARS-CoV-2 inactivated vaccine-induced immunity, but the mechanism of action remains elusive.…”

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

“… 99 Our Tribute patient series was too small to assess associations between patient, tumor, BCG treatment (frequency and dosage), and clinical characteristics and magnitude of TI responses but novel investigations are increasing insight into relevant factors for variation after BCG vaccination. 100 We did find interpatient variation in in vitro cytokine production which may explain the non-statistically significant increases for some cytokines and time points. Surprisingly, increase in H3K4me3 signal at promoters of hallmark TI genes was only observed for less than half of the patients.…”

BCG vaccination induces different mechanisms of mycobacterial growth control compared to natural protection

“…Perhaps this is a reflection of the more resting state of cells in samples that already control, which occurs most frequently in women. In addition, host metabolism at the time of vaccination correlated with trained immunity induced by vaccination 16 . Thus, the host inflammatory and metabolic state may also influence vaccine induced effector responses.…”

“…Finally, participants that reported fever in the 4 weeks preceding study start were excluded from participation. In the present study we analyzed 42 participants of the original study in great detail, these being selected to contain 21 good and 21 poor responders to Staphylococcus aureus (SA) stimulation with IL-1β as biomarker of trained immunity 16 . All 42 participants had samples at baseline and at 3 months.…”

“…β-glucan induced trained immunity showed a clear Warburg effect, high glycolysis and decreased oxidative phosphorylation 15 , whereas BCG induced trained immunity resulted in both increased glycolysis and oxidative phosphorylation 12 . Moreover, host metabolic status at vaccination correlates with trained immunity induction by BCG vaccination 16 .…”