Abstract
Background Mycobacterium tuberculosis (Mtb) is able to evade the immune defenses and may persist for years, decades and even lifelong in the infected host. Mtb cell wall components may contribute to such persistence by modulating several pivotal types of immune cells. Dendritic cells (DCs) are the most potent antigen-presenting cells and hence play a crucial role in the initial immune response to infections by connecting the innate with the adaptive immune system.Principal FindingsWe investigated the effects of two of the major mycobacterial cell wall-associated types of glycolipids, mannose-capped lipoarabinomannan (ManLAM) and phosphatidylinositol mannosides (PIMs) purified from the Mtb strains H37Rv and Mycobacterium bovis, on the maturation and cytokine profiles of immature human monocyte-derived DCs. ManLAM from Mtb H37Rv stimulated the release of pro-inflammatory cytokines TNF, IL-12, and IL-6 and expression of co-stimulatory (CD80, CD86) and antigen-presenting molecules (MHC class II). ManLAM from M. bovis also induced TNF, IL-12 and IL-6 but at significantly lower levels. Importantly, while ManLAM was found to augment LPS-induced DC maturation and pro-inflammatory cytokine production, addition of PIMs from both Mtb H37Rv and M. bovis strongly reduced this stimulatory effect.ConclusionsThese results indicate that the mycobacterial cell wall contains macromolecules of glycolipid nature which are able to induce strong and divergent effects on human DCs; i.e while ManLAM is immune-stimulatory, PIMs act as powerful inhibitors of DC cytokine responses. Thus PIMs may be important Mtb-associated virulence factors contributing to the pathogenesis of tuberculosis disease. These findings may also aid in the understanding of some earlier conflicting reports on the immunomodulatory effects exerted by different ManLAM preparations.
Highlights
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has co-evolved with the human host for millennia [1,2]
These results indicate that the mycobacterial cell wall contains macromolecules of glycolipid nature which are able to induce strong and divergent effects on human Dendritic cells (DCs); i.e while mannose-capped lipoarabinomannan (ManLAM) is immune-stimulatory, phosphatidylinositol mannosides (PIMs) act as powerful inhibitors of DC cytokine responses
PIMs may be important Mtb-associated virulence factors contributing to the pathogenesis of tuberculosis disease
Summary
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has co-evolved with the human host for millennia [1,2]. At the earliest stage of infection mycobacteria-derived molecules, in particular those present in the outermost part of the cell envelope, interact with the cells of the innate immune response, macrophages (MW) and dendritic cells (DCs), and modify their cytokine production pattern, antigen presentation rate and response to T cell-mediated activation, including inhibition of different microbicidal mechanisms [3]. These early interactions of mycobacteria and mycobacteria-derived molecules with host cells are believed to shape and affect the subsequent adaptive immune responses. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a crucial role in the initial immune response to infections by connecting the innate with the adaptive immune system
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