Abstract
Vaccination of infants with bacillus Calmette–Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated in vitro with non-related microbial stimuli. Our aim was to examine an extensive panel of secreted immune biomarkers to characterize the profile of trained innate immunity in infants. Stimulation of whole blood for 48 h was performed 4 months after BCG vaccination, or in control unvaccinated infants. Stimulants were lipopolysaccharide; Pam3Cys (P3C); heat-killed Candida albicans, Staphylococcus aureus, Escherichia coli, and a lysate of Mycobacterium tuberculosis. Culture supernatants were tested for secreted cytokines and chemokines by 42-plex bead array and monocytes and natural killer (NK) cells assessed for expression of activation markers by flow cytometry. BCG-vaccinated infants displayed increases in 11 cytokines and chemokines in response to different non-specific innate immunity stimuli: epidermal growth factor (EGF); eotaxin; IL-6; IL-7; IL-8; IL-10; IL-12p40; monocyte chemotactic protein-3; macrophage inflammatory protein-1α; soluble CD40 ligand and platelet-derived growth factor (PDGF)-AB/BB. Although each stimulant induced a distinct response profile, three analytes, EGF, IL-6, and PDGF-AB/BB, were commonly higher after stimulation with Pam3Cys, C. albicans, and S. aureus. Conversely, certain cytokines such as interferon gamma-inducible protein-10, IL-2, IL-13, IL-17, GM-CSF, and GRO were suppressed in BCG-vaccinated infants, while no increases in TNFα or IL-1β production were detected. We did not observe a concomitant, BCG-associated change in monocyte surface activation markers in response to non-specific stimuli, but we detected a significant increase in CD69 expression on NK cells in response to Pam3Cys. Pam3Cys-induced NK cell activation correlated with the magnitude of IL-12p40 and IL-10 responses to the same stimulant. This study reveals a novel cytokine/chemokine biomarker signature of BCG-induced trained innate immunity in infants and the involvement of NK cells in these responses.
Highlights
Mycobacterium bovis bacillus Calmette–Guérin (BCG) is currently the only licensed vaccine for tuberculosis (TB)
Despite distinct response profiles for each non-specific stimulant, we observed a common signature of increases in epidermal growth factor (EGF), IL-6, and platelet-derived growth factor (PDGF)-AB/BB in response to three different stimulants: Pam3Cys, C. albicans, and S. aureus
If trained innate immunity is to provide a causal link between BCG vaccination of infants and non-specific protection against mortality due to infectious diseases other than those with a mycobacterial etiology [15, 16], a detailed description of the phenomenon in infants and infant cells is needed
Summary
Mycobacterium bovis bacillus Calmette–Guérin (BCG) is currently the only licensed vaccine for tuberculosis (TB). Evidence exists of a beneficial effect for the BCG vaccine against several different diseases and outcomes other than TB, including as a therapeutic agent against bladder cancer when instilled directly into the bladder [13] and protection against all-cause mortality in low birth weight infants [14] These effects are heterologous (non-specific) as they do not rely on mycobacteria-specific adaptive immune responses. The immune responses mediating this effect could be either heterologous T-cells (i.e., T-cells induced by an epitope from one organism but with cross-reactivity to others) or the ability of BCG to potentiate the responsiveness of the innate immune system to later infections: a biological process termed trained innate immunity which represents a de facto innate immune memory [17,18,19] Such a phenomenon is thought to have existed for millions of years as acquired systemic resistance in plants and in invertebrates, neither of which have adaptive immune systems [17]. Studies in adults show that trained innate cells, including monocytes and natural killer (NK) cells, appear to be epigenetically and metabolically reprogrammed to produce increased amounts of pro-inflammatory cytokines and display higher levels of surface activation markers in response to restimulation with toll-like receptor ligands or different whole microorganisms [22,23,24,25]
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