Abstract
BackgroundThe cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. During chronic infection immunosuppressive cytokines are likely to favor mycobacterial growth, persistence, and an avoidance of proper antigen processing and presentation. The activity of interleukin (IL)-27 toward macrophages is anti-inflammatory and this compromises control of mycobacteria. Modulation of the cytokine environment may enhance both protective and vaccine-induced responses.ResultsIn this study we showed that supplying IL-12 and neutralizing IL-27 enhanced acidification and fusion of mycobacterial-containing phagosomes with lysosomes. This was achieved by phagosomal acquisition of vacuolar ATPase (V-ATPase) and CD63. Both V-ATPase and CD63 protein levels were increased by the addition of IL-12 and neutralization of IL-27. In addition, cathepsin D associated with the bacteria and matured to the active form when IL-12 was supplied and IL-27 was neutralized. Lysosomal acidification and cathepsin D activity were associated with control of mycobacteria. The acidification of lysosomes, association with mycobacteria, and maturation of cathepsin D required macrophage production of IFN-γ and signaling through signal transducer and activator of transcription (STAT)-1. In contrast, STAT-3 signaling opposed these events.ConclusionsOur results have identified novel influences of IL-12, IL-27, and STAT-3 on lysosomal activity and further demonstrate that modulating the cytokine environment promotes enhanced trafficking of mycobacteria to lysosomes in human macrophages. This has important implications in approaches to control infection and improve vaccination. Overcoming bacterial resistance to lysosomal fusion may expand the repertoire of antigens presented to the adaptive arm of the immune response.
Highlights
The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages
bacille Calmette-Guerin (BCG) infection of human macrophages increases the production of IL-27 We previously demonstrated that Mycobacterium tuberculosis (MTB) infection induced IL-27 gene expression in human macrophages [17]
Human macrophages were infected with BCG (MOI 10) for 48 h and IL-27 transcripts were analyzed by real time PCR
Summary
The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. The activity of interleukin (IL)-27 toward macrophages is anti-inflammatory and this compromises control of mycobacteria. Modulation of the cytokine environment may enhance both protective and vaccine-induced responses. Several hypotheses have been proposed to explain the limitations of BCG vaccination. These include interference by environmental mycobacteria, genetic differences in the human population, and differences between BCG substrains [4]. It has been proposed that mycobacterial antioxidants, such as iron-cofactored superoxide mutase [5], and secA2 secretion suppress host immunity [6], resulting in reduction of vaccine efficacy. Suppression of host immunity could be mediated by anti-inflammatory cytokines. IL-4 and TGF-β are known to be increased in tuberculosis patients [8]
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