Abstract
Mycobacterium bovis Bacillus Calmette–Guérin (BCG) is a vaccine used to prevent tuberculosis (TB). Due to the poor protection conferred by BCG in adults, new, more effective formulations have been developed. A recombinant BCG vaccine expressing the CMX fusion protein Ag85c_MPT51_HspX (rBCG-CMX) induced Th1 and Th17 responses and provided better protection than BCG. It has been shown that Mycobacterium smegmatis expressing CMX also induces better protection than BCG and is a strong macrophage activator. The aim of the present study was to evaluate macrophage activation by the recombinant CMX fusion protein and by rBCG-CMX and to evaluate their ability to generate vaccine-specific immune responses. The results demonstrate that rCMX protein expressed by BCG (rBCG-CMX) activates pulmonary macrophages; increases the expression of activation molecules, cytokines, and MHC-II. The interaction with rCMX activates the transcription factor NF-κB and induces the production of the cytokines TGF-β, TNF-α, and IL-6. The in vitro stimulation of bone marrow-derived macrophages (BMMs) from TLR-4 or TLR-2 KO mice showed that in the absence of TLR-4, IL-6 was not produced. rBCG-CMX was unable to induce CMX-specific Th1 and Th17 cells in TLR-4 and TLR-2 KO mice, suggesting that these receptors participate in their induction. We concluded that both the rBCG-CMX vaccine and the rCMX protein can activate macrophages and favor the specific immune response necessary for this vaccine.
Highlights
Macrophages are important components of the innate immune response to tuberculosis (TB) because they directly participate in the response to Mycobacterium tuberculosis (Mtb) (Lang, 2013)
The rBCG-CMX vaccine promoted an increase in macrophages with high CD86 and CD206 expression in the lungs of infected animals, indicating a difference in activation from the immune response induced by empty Bacillus Calmette–Guérin (BCG)-pLA71
Previous studies have shown that the rBCG-CMX vaccine induces both Th1 and Th17 responses, and both responses are important in controlling Mtb infection
Summary
Macrophages are important components of the innate immune response to tuberculosis (TB) because they directly participate in the response to Mycobacterium tuberculosis (Mtb) (Lang, 2013). Mtb is an intracellular pathogen that interacts with macrophages and dendritic cells via receptors such as toll-like receptors (TLRs) (Rivera-Marrero et al, 2002; Bafica et al, 2005). Some Mtb proteins, such as ESAT-6, PPE57, Ag85c, and Rv0652, are recognized by TLR-2, CR3, and TLR-4 and modulate macrophage responses (Hetland and Wiker, 1994; Kim et al, 2012; Wang et al, 2012; Xu et al, 2015). ESAT-6, for example, has been shown to modulate macrophages and dendritic cells in vitro, producing cytokines that inhibit Th1 responses and that facilitate Th17 responses (Wang et al, 2012)
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