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Projekt
Macrophage killing mechanisms for intra-phagosomal mycobacteria
Antragsteller
Professor Gareth Griffiths, Ph.D.
Fachliche Zuordnung
Virologie
Förderung
Förderung von 2005 bis 2009
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 14659481
Phagocytosis of pathogens by macrophages forms specialised vesicles, phagosomes. After formation, phagosomes proceed through sequential maturation stages involving fusion, first with early- then with late-endocytic organelles; our studies showed that the latter fusion is facilitated by actin assembly by phagosomal membranes. The fully matured phagosome is a lysosome-like, low pH, hydrolase-rich compartment where final digestion of potential pathogens occurs. Some intraphagosomal pathogens, most prominently Mycobacterium tuberculosis can block phagosome assembly of actin and late fusion events, allowing them to multiply. The applicant¿s group has shown that the addition of pro-inflammatory lipids to infected macrophages can overcome the pathogen-induced block and promote killing of pathogenic mycobacteria. The goal of this proposal is to make a global cell biological analysis of the mechanisms by which macrophages kill intraphagosomal pathogens. Although the dogma that phagosome-¿lysosome¿ fusion is sufficient to kill mycobacteria, the recent work has revealed that, in addition to nitric oxide release, at least four different late endocytic compartments need to fuse with phagosomes in order to kill mycobacteria. These compartments, and their fusion events with phagosomes are functionally distinct, but all are regulated by p38 Map kinase. Further, activation of the pro-inflammatory transcription factor NfKB is also essential for pathogen killing. The interactions between p38 and NfkB with the compartments that fuse with phagosomes to facilitate mycobacterial killing will therefore also be an important aspect f the proposal.
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