Chapter 26 : the Indigestible Microbe

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survives within the phagocytes of its host, yet these cells are key to the effective control of the infection. The macrophage is both an antigen-presenting cell and an immune-effector cell capable of killing if given the correct stimuli. The subtle and not so subtle influence of the host immune system on this environment was demonstrated previously through the regulated expression and dependence on isocitrate lyase (ICL1), the gating enzyme into the glyoxylate pathway. Clemens and Horwitz reported the detection of major histocompatibility complex (MHC) class II molecules in infected macrophages analyzed by immunoelectron microscopy. Researchers went on to confirm that treatment of macrophages with gamma interferon rendered the -containing vacuoles accessible to MHC class II molecules and also H-2M molecules, inferring that activation of the macrophage relocated the pathogen into the antigen-sampling and processing pathway of the cell. It has been shown recently that dendritic cells will present bacterial lipids acquired through internalization of vesicles derived from the apoptotic death of infected bystander macrophages. Macrophages activated by gamma interferon prior to infection deliver the bacteria to acidic, hydrolytically competent lysosomes. The success of as a pathogen hinges on its ability to either modulate or respond to its host cell, the macrophage, throughout the changing phases of the infection in its host.

Citation: Russell D. 2005. the Indigestible Microbe, p 427-436. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch26

Key Concept Ranking

Bacterial Proteins
Class III Phosphatidylinositol 3-Kinase
Bacterial Cell Wall
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Figure 1

Electron micrograph of a murine macrophage infected 4 days previously with . The bacteria reside in membrane-bound vacuoles, many of which remain in tight association with the surface of the bacteria.

Citation: Russell D. 2005. the Indigestible Microbe, p 427-436. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch26
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Image of Figure 2
Figure 2

Immunoelectron micrograph of a murine macrophage infected 4 days previously with , demonstrating that the bacterium-containing phagosomes show minimal interaction with dense lysosomal compartments loaded with biotinylated, mannosylated bovine serum albumin. The infected macrophages were incubated with biotinylated mannosylated bovine serum albumin for 45 min, rinsed, and fixed. The biotinylated, mannosylated bovine serum albumin was detected by incubation of the sections with streptavidin/antistreptavidin and 18-nm-diameter gold particles with conjugated secondary antibody, as detailed previously ( ).

Citation: Russell D. 2005. the Indigestible Microbe, p 427-436. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch26
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Figure 3

Diagram illustrating the major intracellular trafficking pathways that intersect with the vacuoles containing live, virulent bacilli. These vacuoles are accessed by the recycling endosomal system, as evidenced by their acquisition of transferrin. Components of the bacteria released into the bacterium-containing vacuoles traffic out of the vacuoles and coalesce in dense lysosomal compartments. Finally, the bacterium-containing vacuoles, in common with most endosomal-lysosomal stages, show intersection with delivery vesicles derived from the -Golgi network of the host cell.

Citation: Russell D. 2005. the Indigestible Microbe, p 427-436. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch26
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Figure 4

Diagram illustrating the contrasting regulatory pathways proposed to control EEA1 binding to phagosomes. (A) Vergne et al. reported that activity of vps34, a PI 3-kinase, was regulated by calmodulin ( ). They suggested that the bacterial cell wall lipid LAM suppresses the [Ca] flux required to activate vps34 and that therefore no PI 3-P is generated in the membranes of the bacterium-containing phagosomes that fail to acquire EEA1. This model would predict a direct correlation between PI 3-P presence and EEA1 binding. (B) In contrast, Lawe et al. failed to observe any modulation of vps34 activity by calmodulin but found that EEA1 binding was dependent on Ca/calmodulin activation through the IQ domain and other calmodulin-responsive domains ( ). This latter model predicts that PI 3-P presence does not necessarily correspond to EEA1 acquisition.

Citation: Russell D. 2005. the Indigestible Microbe, p 427-436. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch26
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