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¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
Mycobacteria are intracellular pathogens that can survive within macrophage phagosomes. The molecular mechanisms involved in mycobacterial entry are still poorly characterized. We have identified a WD repeat host protein that was recruited to and actively retained on phagosomes by living, but not dead, mycobacteria. This protein, termed TACO, represents a component of the phagosome coat that is normally released prior to phagosome fusion with or maturation into lysosomes. In macrophages lacking TACO, mycobacteria were readily transported to lysosomes followed by their degradation. Expression of TACO in nonmacrophages prevented lysosomal delivery of mycobacteria and prolonged their intracellular survival. Active retention of TACO on phagosomes by living mycobacteria thus represents a mechanism preventing cargo delivery to lysosomes, allowing mycobacteria to survive within macrophages.
We have examined Listeria monocytogenesinfection murine models. As demonstrated by BCGinfection models,
the expression of TACO was induced in macrophages by Listeria infection, suggesting that TACO is involved in the infection by intracellular parasites such as Listeria as well as BCG. However, IFN-gamma stimulation facilitated expression of TACO, indicating that upregulation of TACO expression might be secondary to inflammatory changes. Therefore we focused on BCGinfection models.
We employed TACOtransgenic mice produced by our collaborator, Prof. J Peters in Basel University. Previous data suggested that enhanced expression of TACO may downregulate phagosome-lysosome fusion and may provide disadvantageous effects for infection. Unexpectedly, the numbers of hepatic granulomas in TACO transgenic mice were smaller than those in wild type mice, indicating that transgenic mice were more resistant to BCG infection. Because TACO is a coat protein of phagosomes and closely related to actin fibers, TACO may be involved in not only in the transport of phagosomes but also endocytic function of macrophages. Further studies are undertaken to clarify the function of TACO. Less