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. 2017 Oct 24;8:1368. doi: 10.3389/fimmu.2017.01368

Figure 5.

Figure 5

Mycobacterium tuberculosis interferes with phagosome maturation. M. tuberculosis inhibits acidification by preventing the accumulation of V-ATPase on the phagosome membrane (161), in part through the action of protein tyrosine phosphatase (PtpA) (162). PtpA also dephosphorylates human vacuolar protein sorting 33B (VPS33B) leading to the inhibition of phagosome-lysosome fusion (163). The nucleoside diphosphate kinase (Ndk) is a GAP for Rab5, and by inactivating this GTPase (164), it prevents recruitment of early endosome antigen 1 (EEA1) to the membrane (165). The lipoprotein LprG increases the surface-expression of mannose-capped lipoarabinomannan (ManLAM) (166) and can directly bind to lysosomal-associated membrane proteins (LAMPs) to modulate the traffic machinery of the cell (167, 168). Also, ManLAM (169) and the adhesin PstS-1 (170) bind the mannose receptor, which is involved in the lysosome fusion machinery by an unknown mechanism (171). The mycobacterial glycolipid TDM binds the receptor Monocyte-INducible C-type LEctin (Mincle) (172), activating the SH2-domain-containing inositol polyphosphate 5′ phosphatase (SHP-1) to interfere with phagosome maturation (160). The virulence factor early secretory antigenic target-6 (ESAT-6) inhibits recruitment of Rab7 to the phagosome membrane, preventing autophagy-mediated degradation (173). Also, the secretory acid phosphatase (SapM) direct binds to Rab7 (174) and prevents autophagosome-lysosome fusion (174). In addition, SapM can block the effects of phosphotidylinositol 3-kinase (PI3K) present on phagosomes (158). Upon infection, mycobacteria induce upregulation of several microRNAs (miRNAs) (175–177) and downregulation of others (178) to block autophagy. miR-125a targets UV radiation resistance-associated gene (UVRAG) (176) to block autophagy, while miR-17 activates a protein kinase Cδ (PKCδ)/signal transducer and activator of transcription 3 (STAT3) pathway to regulate autophagy (178). The miR-33 also inhibits fatty acid oxidation to support bacterial replication by a mechanism not yet described (177). How M. tuberculosis alters cell signaling to control miRNAs is not known, but the initial signal might come from TLR2 (176, 179). Finally, the scavenger receptor CD36 participates in surfactant lipid uptake by alveolar macrophages, and M. tuberculosis exploits this function for growth (180).