The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis

Abstract

Mycobacterium tuberculosis (M.tb) survives in macrophages in part by limiting phagosome–lysosome (P-L) fusion. M.tb mannose-capped lipoarabinomannan (ManLAM) blocks phagosome maturation. The pattern recognition mannose receptor (MR) binds to the ManLAM mannose caps and mediates phagocytosis of bacilli by human macrophages. Using quantitative electron and confocal microscopy, we report that engagement of the MR by ManLAM during the phagocytic process is a key step in limiting P-L fusion. P-L fusion of ManLAM microspheres was significantly reduced in human macrophages and an MR-expressing cell line but not in monocytes that lack the receptor. Moreover, reversal of P-L fusion inhibition occurred with MR blockade. Inhibition of P-L fusion did not occur with entry via Fcγ receptors or dendritic cell–specific intracellular adhesion molecule 3 grabbing nonintegrin, or with phosphatidylinositol-capped lipoarabinomannan. The ManLAM mannose cap structures were necessary in limiting P-L fusion, and the intact molecule was required to maintain this phenotype. Finally, MR blockade during phagocytosis of virulent M.tb led to a reversal of P-L fusion inhibition in human macrophages (84.0 ± 5.1% vs. 38.6 ± 0.6%). Thus, engagement of the MR by ManLAM during the phagocytic process directs M.tb to its initial phagosomal niche, thereby enhancing survival in human macrophages.

The innate immune response in human tuberculosis

“…After phagocytosis, Mtb blocks phagosome acidification as well acquisition of hydrolytic enzymes and anti‐microbial peptides. Two major Mtb virulence factors are involved in the blockage of the phagosomal maturation in human cell lines: the glycolipid lipoarabinomannan (LAM) (Hmama et al ., 2004; Kang et al ., 2005; Welin et al ., 2008) and the secreted tyrosine phosphatase (PtpA) (Bach et al ., 2008; Wong et al ., 2011; Wong and Jacobs, 2011). Mtb lacking the surface lipid trehalose dimycolate (TDM) failed to block phagosome maturation in mouse macrophages (Katti et al ., 2008) but to date, this has not been shown in human cells.…”

Pathogen-Derived Oligosaccharides Improve Innate Immune Response to Intracellular Parasite Infection

“…43,44 This pathogen adaptation may allow metacyclic parasites to be briefly present extracellularly after introduction into the host via the vector sand fly, protecting the parasite from complement lysis but also providing a reduced proinflammatory response than would otherwise occur without LPG glycocalyx folding. The trimannose cap on ManLAM has been shown to engage MR, prevent phagolysosomal maturation, 45 and, thus, lead to similar reduced cytokine production. We demonstrated that trimannose-coated beads inhibited IL12p40 through an MR-mediated mechanism, which may help balance signaling mediated through other lectin receptors 36 and allow intracellular survival of M. tuberculosis in macrophages.…”

Lipidomics of host–pathogen interactions

“…Phosphatidylcholine accounts to 75% of total phospholipid [85] GP Viral envelopes are enriched in sphingomyelin [8,86] SP Envelope cholesterol is critical for structure and infectivity [87][88][89] ST 2 Phosphatidylserine stimulates entry of enveloped viruses [90,91] Mannose receptor binds to the ManLAM mannose caps of mycobacteria and mediates phagocytosis [92] GPI anchored proteins (host [35,36] and parasite [37] …”