Interaction ofMycobacterium avium-Containing Phagosomes with the Antigen Presentation Pathway

Abstract

Pathogenic mycobacteria infect macrophages where they replicate in phagosomes that minimize contact with late endosomal/lysosomal compartments. Loading of Ags to MHC class II molecules occurs in specialized compartments with late endosomal characteristics. This points to a sequestration of mycobacteria-containing phagosomes from the sites where Ags meet MHC class II molecules. Indeed, in resting macrophages MHC class II levels decreased strongly in phagosomes containing M. avium during a 4-day infection. Phagosomal MHC class II of early (4 h) infections was partly surface-derived and associated with peptide. Activation of host macrophages led to the appearance of H2-M, a chaperon of Ag loading, and to a strong increase in MHC class II molecules in phagosomes of acute (1 day) infections. Comparison with the kinetics of MHC class II acquisition by IgG-coated bead-containing phagosomes suggests that the arrest in phagosome maturation by mycobacteria limits the intersection of mycobacteria-containing phagosomes with the intracellular trafficking pathways of Ag-presenting molecules.

Phagosomal Processing ofMycobacterium tuberculosisAntigen 85B Is Modulated Independently of Mycobacterial Viability and Phagosome Maturation

“…BMMs do not express MHC-II and must be activated with IFN-␥ to induce MHC-II expression. On the other hand, IFN-␥ promotes phagosome maturation (2,24,26,42,47,48,50), which potentially obscures the effects of M. tuberculosis. Therefore, BMMs were activated with a very low concentration of IFN-␥ (1 U/ml) that was adequate to induce MHC-II expression but still revealed inhibition of phagosomelysosome fusion by live M. tuberculosis (Table 2).…”

“…IFN-␥ has been shown to promote phagosome maturation in different mycobacterial species (2,24,26,42,47,48,50). Fortunately, at the low concentrations of IFN-␥ used to induce MHC-II expression in our BMMs (1 U/ml, 24 h) and within the time that BMMs were incubated with M. tuberculosis (2 h), IFN-␥ did not increase localization of the LysoTracker dye with live M. tuberculosis phagosomes ( Table 2) While most phagosomes containing dead M. tuberculosis preparations (HK, RadK, and RifK) colocalized with the LysoTracker dye, most phagosomes containing live M. tuberculosis preparations did not ( Table 2).…”

Cellubrevin Alterations and Mycobacterium tuberculosis Phagosome Maturation Arrest

“…These processes are sometimes targeted by a class of microbes capable of affecting phagosome integrity or maturation (8, 10 -19). Interference with the normal pathway of phagosomal maturation into the phagolysosome enables such intracellular pathogens to avoid microbial growth control or killing by the host phagocytic cells or to avert efficient antigen presentation to the effectors of adaptive immune response in the host (1,3,7,20,21). Consequently, investigations of microbial interference with the trafficking processes in the host cells may provide a means for dissecting the phagosomal maturation pathway.…”

Alternate Class I MHC Antigen Processing Is Inhibited by Toll-Like Receptor Signaling Pathogen-Associated Molecular Patterns:Mycobacterium tuberculosis19-kDa Lipoprotein, CpG DNA, and Lipopolysaccharide

“…Phagosomes undergo a process of maturation, which involves fusion with lysosomes and acquisition of lysosomal markers and proteases. MTB is known to inhibit phagosome maturation (42)(43)(44)(45)(46)(47)(48), but the mechanism for this inhibition is unknown. To assess modulation of phagosome maturation and Ag catabolism, macrophages were incubated with IFN-␥ and MTB 19-kDa lipoprotein, exposed to latex-OVA, and homogenized; phagosomes were prepared and analyzed by flow organellometry (36,37).…”