title: Why intracellular parasitism need not be a degrading experience for Mycobacterium.
abstract: The success of mycobacteria as pathogens hinges on their ability to infect and persist within the macrophages of their host. However, activation of host macrophages by cytokines from a productive cellular immune response can stimulate the cells to kill their resident pathogens. This suggests that the interaction between host cell and microbe is in delicate balance, which can be tipped in favour of either organism. Biochemical analysis of mycobacterial vacuoles has shown them to be integral to the host cell's recycling endosomal system. As such they show limited acidification and hydrolytic activity despite possession of known lysosomal constituents such as cathepsins D, B and L, and LAMP 1. Even in established infections, they remain dynamic compartments accessible to several plasmalemma-derived constituents. Once the macrophage has been activated by IFN-gamma and TNF-alpha the vacuoles coalesce and acidify. This marks a distinct alteration in vacuole physiology and leads to stasis and death of the mycobacteria. Mycobacteria have developed several strategies to avoid this outcome. Most notably, live bacilli-induce sustained release of IL-6 from infected macrophages. IL-6 blocks the ability of both polyclonal primary T cells and T-cell hybridomas to respond to appropriate stimuli. Such an activity could render the centres of infection foci, such as granulomas, anergic and thus avoid release of macrophage-activating cytokines. This paper discusses both the mechanisms by which mycobacteria try to ensure their success as intracellular pathogens and the relevance of these strategies to the overall understanding of mycobacterial diseases.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110, USA. russell@borcim.wustl.edu
authors.forename: D G
authors.initials: DG
authors.lastname: Russell
authors.forename: S
authors.initials: S
authors.lastname: Sturgill-Koszycki
authors.forename: T
authors.initials: T
authors.lastname: Vanheyningen
authors.forename: H
authors.initials: H
authors.lastname: Collins
authors.forename: U E
authors.initials: UE
authors.lastname: Schaible
mesh_terms: D011992:Endosomes / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D009161:Mycobacterium / Q000472:pathogenicity* / Q000502:physiology*; D009164:Mycobacterium Infections / Q000382:microbiology*; D014617:Vacuoles / Q000378:metabolism*
chemical_list: D015850:Interleukin-6