Playing hide-and-seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenolic glycolipids

Abstract

Mycobacterial pathogens, including Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), have evolved a remarkable ability to evade the immune system in order to survive and to colonize the host. Among the most important evasion strategies is the capacity of these bacilli to parasitize host macrophages, since these are major effector cells against intracellular pathogens that can be used as long-term cellular reservoirs. Mycobacterial pathogens employ an array of virulence factors that manipulate macrophage function to survive and establish infection. Until recently, however, the role of mycobacterial cell envelope lipids as virulence factors in macrophage subversion has remained elusive. Here, we will address exclusively the proposed role for phthiocerol dimycocerosates (DIM) in the modulation of the resident macrophage response and that of phenolic glycolipids (PGL) in the regulation of the recruitment and phenotype of incoming macrophage precursors to the site of infection. We will provide a unique perspective of potential additional functions for these lipids, and highlight obstacles and opportunities to further understand their role in the pathogenesis of TB and other mycobacterial diseases.

Keywords: immune responses; lipids; macrophages; mycobacteria; pathogens; virulence.

Figure 1

Structures of DIM and PGL produced by various mycobacterial species. (A) Structure of the major DIM and PGL lipid moieties. The lipid core is composed of a long-chain β-diol (phthiocerol and phenolphthiocerol), showing slight length variations (see m1 and m2 values in embedded table), esterified by polymethyl-branched fatty acids. In most cases, the configuration of the asymmetric centers bearing the methyl branches (asterisks) are of the D series, mycocerosic acids, but in a limited number of mycobacterial species, they belong to the L series and are then called phthioceranic acids (see table). Minor structural variants of the β-diol can contain a keto group in place of the methoxy group. (B) Structure of the species-specific sugar moiety of the major forms of PGL produced by Mtb (PGL-Tb1), M. marinum (PGL-mar) and M. leprae (PGL-1). Rhamnose is represented in green, fucose in orange and glucose in blue.

Figure 2

Putative molecular mechanisms through which DIM and PGL remodel macrophage activity during the early steps of infection. When mycobacteria encounter macrophages, they use cell surface exposed PAMPs to recognize numerous plasma membrane PRRs, such as TLR (e.g., TLR-2) and carbohydrate-recognition receptors (e.g., CR3 or other lectin receptors). (A) During bacterial recognition, DIM exert a masking effect on PAMPs, thereby preventing TLR-2 detection and triggering of subsequent bactericidal and immune responses. DIM could also insert into plasma membrane, changing its biophysical properties in a manner that increases CR3-mediated bacteria uptake, and decreases bactericidal functions. Likewise, DIM could insert within intracellular membranes (e.g., phagosomal membranes) where they collaborate with ESAT-6 to increase its membrane lytic activity, thereby inducing membrane damage and consequently allowing mycobacteria to escape into the cytosol. Altogether, DIM-mediated effects may lead to mycobacteria replication and innate immune evasion. (B) Some PGL species, such M. leprae PGL-1 and potentially Mtb PGL-Tb1, are able to decrease host immune response either by direct inhibition of TLRs or by taking advantage of lectin receptor (e.g., CR3) capacity to interfere with TLR-triggered pro-inflammatory cytokine secretion (e.g., TNF-α). They may also exploit these lectin receptors to promote mycobacterial uptake by macrophages. In the case of PGL-mar, a putative “PGL receptor” at the surface of epithelial cells has been proposed to be responsible for the induction of CCL2, and the subsequent macrophage recruitment.