BCG-Induced Trained Immunity in Healthy Individuals: The Effect of Plasma Muramyl Dipeptide Concentrations.

Vera P Mourits,Wern Cui Chu,Mihai G Netea,Helga Dijkstra,Heidi Lemmers,L Charlotte J De Bree,Yue Wang,Xiaoli Xu,Valerie A C M Koeken,Reinout Van Crevel,Simone J C F M Moorlag,Leo A B Joosten

doi:10.1155/2020/5812743

Abstract

BCG vaccination protects not only against tuberculosis but also against heterologous infections. This effect differs between individuals, yet the factors responsible for this variation are unknown. BCG-induced nonspecific protection is, at least partially, mediated by innate immune reprogramming (trained immunity), which can be induced by the muramyl dipeptide (MDP) component of peptidoglycans. We aimed to study whether differential release of MDP in healthy individuals may explain variability of their response to BCG vaccination. Circulating MDP concentrations were increased up to three months after BCG vaccination. MDP concentrations at baseline, but not their increase postvaccination, positively correlated with the induction of trained immunity and not with mycobacteria-induced T-cell responses. Interestingly, MDP concentrations correlated with inflammatory markers in the circulation. In conclusion, circulating MDP concentrations are associated with the strength of trained immunity responses and thus influence the biological effects of BCG vaccination. This study increases our understanding about the role of MDP in BCG-induced trained immunity, which might help to optimize vaccine efficacy and explore novel applications of BCG vaccination.

Highlights

The Bacillus Calmette-Guérin (BCG) vaccine is a liveattenuated vaccine that protects against tuberculosis, one of the world’s deadliest infectious diseases [1]
muramyl dipeptide (MDP) concentrations in the circulation were measured in the serum of 321 healthy individuals of the 300BCG cohort (aged 18-75 years, 57% women, 83% body mass index (BMI) between 18.5 and 25 (Figure 2(a)))
Since MDP is able to induce chemokine and cytokine production in vitro, in synergy with other stimuli [14], we investigated whether MDP concentrations in vivo correlate with cytokine production upon ex vivo Peripheral blood mononuclear cells (PBMCs) stimulation with the nonspecific stimulus S. aureus or specific stimulus M. tuberculosis

Summary

Introduction

The Bacillus Calmette-Guérin (BCG) vaccine is a liveattenuated vaccine that protects against tuberculosis, one of the world’s deadliest infectious diseases [1]. It has been shown that BCG vaccination, besides its effects for the prevention of tuberculosis, reduces allcause morbidity and mortality in children and neonates, especially by protecting against heterologous infections [2]. This nonspecific protection could, at least partially, be explained by induction of trained immunity [3]. This is a process of innate immune cell reprogramming, a de facto nonspecific innate immune memory, in which certain infections and vaccinations induce an enhanced inflammatory response in innate immune cells upon restimulation with an unrelated infectious agent. Trained immunity responses induced by BCG vaccination were shown to be dependent on the engagement of the intracellular receptor nucleotidebinding oligomerization domain 2 (NOD2) by the peptidoglycan component muramyl dipeptide (MDP) [5]

Objectives

Methods

Results

Discussion

Conclusion