Abstract
Bacillus Calmette–Guérin (BCG) is used as a vaccine and diagnostic test for tuberculosis, as well as immunotherapy in the treatment of bladder cancer. While clinically useful, the response to mycobacterial stimulation is complex and the induced protein signature remains poorly defined. We characterized the cell types directly engaged by BCG, as well as the induced cytokine loops that transmit signal(s) to bystander cells. Standardized whole-blood stimulations and mechanistic studies on single and purified cell populations identified distinct patterns of activation in monocytes as compared to neutrophils and invariant lymphocyte populations. Deconvoluting the role of Toll-like receptor 2/4 and Dectin-1/2 in the inflammatory response to BCG, we revealed Dectin-1/2 as dominant in neutrophils as compared to monocytes, which equally engaged both pathways. Furthermore, we quantified the role of NF-κB and NADPH/reactive oxygen species (ROS)-dependent cytokines, which triggered a JAK1/2-dependent amplification loop and accounted for 40–50% of the induced response to BCG. In sum, this study provides new insight into the molecular and cellular pathways involved in the response to BCG, establishing the basis for a new generation of immunodiagnostic tools.
Highlights
The bacillus Calmette–Guérin (BCG) vaccine strain has been used for the prevention of childhood tuberculosis (TB) for more than 90 years
We investigated the engagement of selected host receptors by BCG [e.g., the principle toll-like receptors (TLRs), TLR2 and TLR4], as well as the C-type lectin-like receptors (CLRs) Dectin-1/2, which have been reported to be involved in mycobacteria–host cells interaction [7, 9, 10], and the key innate cytokines [e.g., IL-6, tumor necrosis factor-alpha (TNF-α), and IL-1β], which may mediate a feed-forward host response
We investigated the sequential secretion of these proteins, measured after whole-blood stimulation of five healthy donors, comparing BCG and null conditions during a 30 h time course (Figures 1B–D)
Summary
The bacillus Calmette–Guérin (BCG) vaccine strain has been used for the prevention of childhood tuberculosis (TB) for more than 90 years. It is one of the most widely used vaccines, delivered to >80% of neonates and infants worldwide [1]. One advance has been the introduction of two ex vivo interferon gamma release assays (IGRAs) to replace the use of the purified peptide derivative skin test [5]. Both IGRAs are assessed based on IFN-γ production: the number of TB antigen-specific T cells producing IFN-γ for T-SPOT.TB
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