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Maximiliano Gutierrez group project:

The host perspective: understanding phagosome biology and immune control of phagosome maturation

The aim of our research is to give insights into the host factors that facilitate mycobacterial killing. The exact mechanisms that govern this initial sterilizing reaction are not completely understood. Understanding therefore how host cells eliminate mycobacteria is important to find possible therapeutic strategies that enhance this natural response.

The phagosome is a key organelle that links innate and adaptive immunity. The phagosome that contains mycobacteria is a fascinating compartment customized by the bacteria for its own benefit. Understanding how the circuits between mycobacteria and phagosomal milieu signals are established is crucial. Not only because in some cases this response is effective but also because in case of persistence, the mycobacteria/phagosome interface must be maintained through time.

We have identified a large number of membrane trafficking regulatory proteins regulated at the transcriptional level via NF-kB during the early killing of mycobacteria by macrophages. This argues that NF-kB participates in the early steps of the innate immune response altering the levels of proteins that regulates phagolysosome biogenesis (Gutierrez et al. 2008; Gutierrez et al. 2009). The most promising candidate proteins are membrane trafficking proteins and lysosomal receptors. However, the exact role of many of these proteins in phagosome maturation and innate immunity is unknown.

We aim to define the function of these proteins during phagocytosis and evaluate the impact on the innate immune response to M. tuberculosis. For one of the identified proteins, sortilin, we have already shown its role during phagosome maturation. We identified a novel pathway by which selected proteins are transported to the phagosome bypassing lysosomes during maturation of phagosomes (Wähe et al. 2010).

We expect that the knowledge emerging from our studies will identify critical host anti-mycobacterial factors. The characterization of those factors will highlight attractive targets subverted by intracellular mycobacteria to develop new strategies to combat tuberculosis.