Cord factor trehalose 6,6′-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages

Abstract

The persistence of tuberculosis within pulmonary granulomatous lesions is a complex phenomenon, with bacterial survival occurring in a focal region of high immune activity. In part, the survival of the organism may be linked to the ability of the surface glycolipid trehalose 6,6′-dimycolate (TDM; cord factor) to inhibit fusion events between phospholipid vesicles inside the host macrophage. At the same time, TDM contributes to macrophage activation and a cascade of events required for initiation and maintenance of granulomatous responses. This allows increased sequestration of organisms and further survival and persistence within host tissues. Bacterial viability, macrophage cytokine and chemokine response, and intracellular trafficking were investigated in Mycobacterium tuberculosis from which TDM had been removed. Removal of surface lipids led to enhanced trafficking of organisms to acidic compartments; reconstitution of delipidated organisms with either pure TDM or the petroleum ether extract containing crude surface lipids restored normal responses. Use of TDM-coated polystyrene beads demonstrated that TDM can mediate intracellular trafficking events, as well as influence macrophage production of pro-inflammatory molecules. Thus, the presence of TDM may be an important determinant for successful infection and survival of M. tuberculosis within macrophages.

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

“…Infection with Mycobacterium bovis Calmette Guerin (BCG), Pasteur strain TMC 1011 was accomplished as reported previously [26]. Briefly, organisms were grown in Dubos base (without addition of glycerol) with 10% supplement (5% BSA and 7.5% dextrose in saline) on an orbital shaker at 37°C for 2 weeks before use.…”

LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest

“…The mechanisms involved in phagosome maturation arrest are still elusive. Phagosome maturation arrest is in part dependent on lipid components of the mycobacterial cell wall, such as lipoarabinomannan, phosphatidylinositol mannosides (PIMs) and cord factor (Anes et al, 2003;Fratti et al, 2001Fratti et al, , 2003Indrigo et al, 2003;Vergne et al, 2003Vergne et al, , 2004. Additional factors involved are the acid phosphatase SapM (Saleh & Belisle, 2000;Vergne et al, 2005), the bacterial serine/threonine kinase PknG (Walburger et al, 2004), and the zinc-metalloprotease Zmp1 (Master et al, 2008).…”

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…TDM has also been shown to have adjuvant properties generating an optimal antibody response (Bekierkunst et al, 1971b) and a non-specific immune response against bacterial infections and parasitic infections ( Bekierkunst, 1968;Parant et al, 1977Parant et al, , 1978Ribi et al, 1976;Yarkoni & Bekierkunst, 1976). Recent studies uncover that TDM is actively participating in blocking the mycobacterial phagosome maturation (Indrigo et al, 2003). Inhibition of the phagosome maturation is observed after phagocytosis of virulent strains of M.tb, allowing the bacillus to survive within the phagocyte (Schlesinger LS et al, 2008).…”