de Chastellier Chantal, Forquet Frédérique, Gordon Alon, Thilo Lutz
Aix Marseille Université, Faculté des Sciences de Luminy, UMR 6546, Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, F-13288, France.
Cell Microbiol. 2009 Aug;11(8):1190-207. doi: 10.1111/j.1462-5822.2009.01324.x. Epub 2009 Apr 7.
Pathogenic mycobacteria survive in macrophages of the host organism by residing in phagosomes which they prevent from undergoing maturation and fusion with lysosomes. Several molecular mechanisms have been associated with the phagosome maturation block. Here we show for Mycobacterium avium in mouse bone marrow-derived macrophages that the maturation block required an all-around close apposition between the mycobacterial surface and the phagosome membrane. When small (0.1 microm) latex beads were covalently attached to the mycobacterial surface to act as a spacer that interfered with a close apposition, phagosomes rapidly acquired lysosomal characteristics as indicators for maturation and fusion with lysosomes. As a result, several mycobacteria were delivered into single phagolysosomes. Detailed electron-microscope observations of phagosome morphology over a 7-day post-infection period showed a linear correlation between bead attachment and phagosome-lysosome fusion. After about 3 days post infection, conditions inside phagolysosomes caused a gradual release of beads. This allowed mycobacteria to re-establish a close apposition with the surrounding membrane and sequester themselves into individual, non-maturing phagosomes which had lost lysosomal characteristics. By rescuing themselves from phagolysosomes, mycobacteria remained fully viable and able to multiply at the normal rate. In order to unify the present observations and previously reported mechanisms for the maturation block, we discuss evidence that they may act synergistically to interfere with 'Phagosome Membrane Economics' by causing relative changes in incoming and outgoing endocytic membrane fluxes.
致病性分枝杆菌通过驻留在吞噬体中而在宿主生物体的巨噬细胞内存活,它们可阻止吞噬体成熟并与溶酶体融合。几种分子机制与吞噬体成熟阻滞有关。在此我们发现,在小鼠骨髓来源的巨噬细胞中,鸟分枝杆菌的成熟阻滞需要分枝杆菌表面与吞噬体膜全面紧密贴附。当将小的(0.1微米)乳胶珠共价连接到分枝杆菌表面作为间隔物来干扰紧密贴附时,吞噬体迅速获得溶酶体特征,作为成熟和与溶酶体融合的指标。结果,多个分枝杆菌被递送到单个吞噬溶酶体中。在感染后7天内对吞噬体形态进行的详细电子显微镜观察显示,珠子附着与吞噬体 - 溶酶体融合之间存在线性关系。感染后约3天,吞噬溶酶体内的条件导致珠子逐渐释放。这使得分枝杆菌能够与周围膜重新建立紧密贴附,并将自身隔离到已失去溶酶体特征的单个非成熟吞噬体中。通过从吞噬溶酶体中自我解救,分枝杆菌保持完全存活并能够以正常速率繁殖。为了统一目前的观察结果和先前报道的成熟阻滞机制,我们讨论了相关证据,即它们可能通过引起内吞膜通量的进出相对变化而协同作用,干扰“吞噬体膜经济学”。