CELL BIOLOGY OFMYCOBACTERIUM TUBERCULOSISPHAGOSOME

Abstract

Phagocytosis and phagolysosome biogenesis represent fundamental biological processes essential for proper tissue homeostasis, development, elimination of invading microorganisms, and antigen processing and presentation. Phagosome formation triggers a preprogrammed pathway of maturation into the phagolysosome, a process controlled by Ca2+ and the regulators of organellar trafficking centered around the small GTP-binding proteins Rabs and their downstream effectors, including lipid kinases, organellar tethering molecules, and membrane fusion apparatus. Mycobacterium tuberculosis is a potent human pathogen parasitizing macrophages. It interferes with the Rab-controlled membrane trafficking and arrests the maturing phagosome at a stage where no harm can be done to the pathogen while the delivery of nutrients and membrane to the vacuole harboring the microorganism continues. This process, referred to as the M. tuberculosis phagosome maturation arrest or inhibition of phagosome-lysosome fusion, is critical for M. tuberculosis persistence in human populations. It also provides a general model system for dissecting the phagolysosome biogenesis pathways. Here we review the fundamental trafficking processes targeted by M. tuberculosis and the mycobacterial products that interfere with phagosomal maturation.

Porins limit the intracellular persistence of Mycobacterium smegmatis

“…The chemical composition of a phagosome depends, among other factors, on the phagocytosed bacterium. The stage of maturation of the phagosome in turn determines the degree to which the resident bacteria are exposed to acidic conditions, hydrolytic enzymes, cationic antimicrobial peptides and reactive oxygen and nitrogen compounds on the one hand, and the degree to which they have access to nutrients on the other (Schnappinger et al, 2003;Vergne et al, 2004). The survival of an intraphagosomal bacterium depends on the balance between these antimicrobial activities and nutrient supply, which may both be influenced by the amount of porins present in the otherwise extremely impermeable cell wall of mycobacteria.…”

“…The cell wall constituent lipoarabinomannan (LAM) interferes with acquisition of late endosomal constituents (Fratti et al, 2003), and by this means the bacteria are not exposed to the antimicrobial activities of the macrophage. Another glycolipid, phosphatidylinositol mannoside (PIM), on the other hand, stimulates fusion with early endosomal compartments, thereby ensuring access to endocytosed nutrients, including iron (Vergne et al, 2004). In this situation, the advantage of an enhanced nutrient supply brought about by additional porins may outweigh the disadvantage of reduced protection against antimicrobial activities.…”

The C‐terminal of CysM from Mycobacterium tuberculosis protects the aminoacrylate intermediate and is involved in sulfur donor selectivity

“…During primary tuberculosis infection and in the persistent state Mycobacterium tuberculosis survives within macrophages in phagosomes where the environment is characterized by low nutrient and oxygen supply, exposure to hydrogen peroxide and reactive oxygen and nitrogen intermediates [1,2]. These compounds are used by phagocytic cells to eliminate internalized bacteria [3,4], but several pathogens, for instance Salmonella typhimurium and M. tuberculosis, are able to escape elimination which leads to long term survival and persistent infection [5].…”

Alteraciones en el reclutamiento y activación de proteínas Rab durante la infección micobacteriana

“…Además, Mycobacterium spp. inhibe tempranamente la acidificación de los fagosomas que lo contienen, escapando de los mecanismos bactericidas que poseen estas células, evadiendo el sistema inmunitario y sobreviviendo dentro del huésped (43).…”