Interaction between innate immune cell receptors and Mycobacterium tuberculosis.

Introduction: Tuberculosis is still a leading cause of bacterial infection worldwide, with an estimate of over two billion people latently infected with Mycobacterium tuberculosis (MTB). A delicate interplay between MTB and the host’s innate and acquired immune system can influence the outcome of the infection, which ranges from pathogen elimination to the establishment of a latent infection or a progressive disease. Although the host cell-mediated adaptive immune response is of vital importance in the control of MTB infection, growing evidence indicates innate immunity as an important arm of antimycobacterial host defence mechanism that senses various pathogen-associated molecular patterns (PAMP) of microbes by a variety of pattern recognition receptors (PRRs). Among PRRs, Toll-like receptors (TLRs), Nucleotide Oligomerization Domain (NOD)-like receptors and C-type lectins have been implicated in recognition of mycobacteria and in the initiation of the immune activation. Materials and Methods: Human innate immune cells (i.e. monocyte derived dendritic cells (DC) and macrophages, NK cells) were stimulated in vitro with whole mycobacteria, with a MTB H37Rv mutant strain in which the gene rv1794 at the ESX-5 locus was inactivated (Mtbrv1794ko), or with mycobacterial cell-wall components (CWC), and the cytokine production and the expression of activation markers were analyzed. In addition, binding of MTB CWC to soluble PRRs (e.g. TLR2, Natural Cytotoxicity Receptors [NCRs]) were assessed by ELISA. Results: MTB preferentially induced production of IL-23 but not IL-12 from infected DC, similarly to the stimulation of such cells with NOD and TLR2 ligands. DC priming with IFN-g strongly increased IL-12 production, a pivotal cytokine in immunity against pathogens. The macrophages infected with Mtbrv1794ko produced significantly higher amounts of the pro-inflammatory cytokine IL-1b as compared to wild type MTB suggesting that Rv1794 might be involved in the modulation of IL-1b production from human macrophages. Finally, mycobacteria directly induced the proliferation, IFN-g production, and cytotoxic activity of NK cells. Further experiments demonstrated that CWC were able to bind to NCR NKp44 (arabinogalactan, mycolic acids) and TLR2 (peptidoglycan), respectively, and the interaction of TLR2 with peptidoglycan promoted activation of resting NK cells and IFN-g production. Discussion and Conclusion: The differential ability of pathogens to induce innate immune cells to produce cytokines regulates the immune response to infection. A successful outcome of the immune response to MTB largely depends on the initial phases of the infection when cells of innate immunity recognize the PAMPs of MTB by their PRRs and mount a correctly orchestrated cytokine production.