Mycobacterium tuberculosis and myeloid-derived suppressor cells: Insights into caveolin rich lipid rafts

Abstract

Mycobacterium tuberculosis (M.tb) is likely the most successful human pathogen, capable of evading protective host immune responses and driving metabolic changes to support its own survival and growth. Ineffective innate and adaptive immune responses inhibit effective clearance of the bacteria from the human host, resulting in the progression to active TB disease. Many regulatory mechanisms exist to prevent immunopathology, however, chronic infections result in the overproduction of regulatory myeloid cells, like myeloid-derived suppressor cells (MDSC), which actively suppress protective host T lymphocyte responses among other immunosuppressive mechanisms. The mechanisms of M.tb internalization by MDSC and the involvement of host-derived lipid acquisition, have not been fully elucidated. Targeted research aimed at investigating MDSC impact on phagocytic control of M.tb, would be advantageous to our collective anti-TB arsenal. In this review we propose a mechanism by which M.tb may be internalized by MDSC and survive via the manipulation of host-derived lipid sources.

Keywords: Caveolin; Internalization; Lipid metabolism; Mycobacterium tuberculosis; Myeloid-derived suppressor cells.

Fig. 1

Conceptual demonstration of the proposed internalization mechanism employed by Mycobacterium tuberculosis (M.tb) to enter myeloid-derived suppressor cells (MDSC) in order to evade traditional entry mechanisms whereby lysosomal fusion and subsequent mycobacterial degradation is averted. Lipid receptors found on the surface of M.tb bacilli bind to various receptors found within and neighbouring lipid-raft domains on the surace of MDSC plasma membranes which are known to contain GPI-anchored proteins, cav-1 proteins and receptors like complement receptor 3 (CD3/CD11b). These receptors bind pathogenic molecules along with pattern recognition receptors, like those from the toll-like-receptor family, which are located close to these lipid-raft regions (insert). Binding of the receptors within the lipid-rafts activates cholesterol accumulation and subsequent spontaneous curvature of the membrane, facilitated mainly by the cav-1 proteins. We propose that this process may result in the complete or partial engulfment of individual bacilli into lipid-rich cells like MDSC, and support pathogen growth and survival through the prevention of lysosomal fusion to these endocytic vesicles (caveosomes). It is not yet known biologically how this is achieved; as such outstanding questions remain as to whether these structures partially or fully surround bound bacteria, how they achieve this, or if they recruit multiple lipid-rafts to a single bacillus for complete encapsulation.