Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages¹

Cell, Vol. 119, 753-766(2004)

Speaker: 李璟采                         Time:15:10~16:10, May 11, 2005

Commentator: 林以行 老師                Place:Room601

Abstract:

Mycobacterium tuberculosis is an intracellular pathogen existing in the phagosomes by interference with phagosome-lysosome fusion. This organism employs the reduction of H⁺-ATPase level² and inhibition of phosphatidylinositol 3-phosphate (PI3P)-dependent trafficking pathways in the infected macrophage to reduce the acidification of phagosome³. The production of PI3P via the type III PI3K, hVPS34, is essential for autophagy, an intracellular pathway for programmed turnover of long-lived cytoplamic macromolecules and organelles in response to starvation. Autophagy in mammalian cells acquires endosomal and lysosomal characteristics and can be induced by rapamycin, an inhibitor of Tor, which controls cell growth in response to nutrients. The progression of autophagy is sensitive to wortmannin and 3-methyladenine (3MA), the inhibitors of PI3K. Because PI3P is involved in both the phagosomal maturation and autophagy pathways, the authors intented to determine whether the induction of autophagy may influence the maturation of mycobacterial phagosomes. They found that both the induction of autophagy by starvation or rapamycin can enhance mycobacterial phagosome acidification and promote maturation of maycobacterial phagosomes. They further demonstrated that starvation promoted the recruitment of critical autophagy effectors to mycobacterial phagosomes. In addition , the induction of autophagy by starvation or rapamycin can override the mycobacterial block of phagolysosome biogenesis in RAW cells , murine bone marrow-derived macrophages (BMM), and human peripheral blood monocyte-derived macrophages (MDM) infected by either BCG or virulent M. tuberculosis. Finally, they found that the stimulation of IFN-γ induced by M. tuberculosis resulted in autophagy in phagocytic cells. These results suggest that stimulation of autophagy by physiological or pharmacological means may promote the maturation of mycobacterial phagosomes and overcomes the M. tuberculosis-induced inhibition of phagolysosome biogenesis.

References:

1.     Gutierrez M. G., et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753-766.(2004)

2.     Sturgill-Koszycki, S., et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263, 678-681(1994)

3.     Fratti, R.A., et al. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. PNAS 100, 5437–5442.(2003)