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In a classic example of microbiological payback, mycobacteria have evolved the ability to parasitize macrophages, cells that ordinarily digest bacteria circulating in the blood. After a macrophage endocytoses a mycobacterium, the resulting phagosome deviates from the normal maturation process and becomes a safe haven for the pathogen rather than an acidic digestive compartment for the macrophage. Fratti et al. (page 631) used this system to dissect the molecular mechanism of phagosome biogenesis, providing important new insights into phagosomal maturation and mycobacterial pathogenesis.
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1 L6 x- r' H) K- X ]Phagosomes containing latex beads recruit EEA1, a Rab5 effector and regulator of vesicular trafficking, but phagosomes containing mycobacteria exclude this protein. The authors attempted to make the latex-bead phagosomes behave like mycobacteria-containing phagosomes, and found that inhibitors of PI-3-kinase activity or microinjection of antibodies against EEA1 and the PI-3-kinase hVPS34 inhibited the acquisition of late endocytic markers. Coating the latex beads with ManLAM, a lipid isolated from Mycobacterium tuberculosis, also inhibited EEA1 recruitment to the phagosomes and prevented them from maturing.
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: x2 u/ ?" h- d! ]/ @0 C# ^2 E' wEEA1 is believed to be required for trafficking between the trans-Golgi network (TGN) and endosomes. The new data suggest that mycobacteria prevent phagosomal acidification by blocking TGN interactions, which are required for fusion with H ATPase-containing vesicles. The work is also the first demonstration that a phospholipid produced by a pathogen can redirect normal phagosomal trafficking. Results from other studies on EEA1 distribution in infected cells suggest that similar mechanisms may be used by mycobacteria, Leishmania donovani, and Human Granulocytic Ehrlichiosis Agent, raising the possibility that therapies targeting this pathway could be useful against several important intracellular pathogens.(EEA1 is recruited to normal phagosomes () |
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发表于 2009-3-5 23:37
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