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Friday, May 7, 2010
Innate Immunity, Learning on the Fly
We use both mammalian systems and model organisms, and focus on developing new systems-based approaches to understand phagocytosis and innate immunity. Our ultimate aim is to generate and test novel hypotheses concerning the host-pathogen interaction and the role of phagocytosis in development and host defense. Particular areas of interest are:
The role of phagocytosis in innate immune sensing
We are interested in defining the role of phagocytic receptors and opsonins in regulating innate immune sensing by pattern recognition receptors. We have focused on the role of a soluble host defense molecule, the mannose binding lectin (in collaboration with K. Takahashi of the Massachusetts General Hospital) and the type B scavenger receptor, CD36 (in collaboration Kathryn Moore, NYU). These molecules are evolutionarily ancient and highly conserved among species, and hence are useful in establishing the paradigms and common themes for how innate immune sensing is regulated. We have defined a role for both of these molecules in regulating signalling from the archetypal pattern recognition receptors, the toll-like receptors. In addition, we are interested in understanding the role of phagocytosis in ligand delivery to the cytosolic pattern recognition receptors, the NOD/NLRs. What appears to be a common emerging theme from this work is that engulfment greatly increases the efficiency of pathogen sensing. Thus phagocytosis plays an important role not only in killing engulfed bacteria but also in sensing and initiating the appropriate response. (Stuart et al, JCB 2005; Ip et al, JEM, 2008; Ip et al J Immunol, 2010 in press; Stewart, Stuart et al, Nature Immunology, 2010)
The use of model organisms to study phagocytosis and non-TLR host defense pathways
The major tools used by the laboratory to understand phagocytosis and innate immune sensing are genetically tractable model organisms such as Drosophila melanogaster (in collaboration with C Kocks, MGHfC (Kocks et al, Cell 2005). We are particularly interested in defining the function of non-TLR pathways in host defense, and these organisms offer a simple system in which these pathways can be defined. As an example, we have identified the importance for certain Rho-GTPases that we believe act as evolutionarily ancient innate immune molecules. (Charriere et al, JBC 2010 in press; Boyer et al, under review)
Drosophila as a model system to study phagocytosis. Fluorescent bacteria injected into fruitflies concentrate in phagocytes lining the dorsal vessel.
The use of computational modelling to understand the cell biology and evolutionary origins of the phagosome
We have developed an interdisciplinary approach to study the phagosome that utilises proteomics, computational modelling and functional genomics to understand the organization of this organelle. This work has been performed in close collaboration with Michel Desjardins of the University of Montreal and with Joel Bader of Johns Hopkins University. As an important part of this work we have generated a Drosophila RNAi collection of enriched dsRNAs targeting molecules involved in phagocytosis. This collection is of particular use in studying proteins involved in the engulfment and destruction of bacteria in high-throughput RNAi screens. We are currently extending the model we have developed to address the evolutionary origins of phagocytosis by comparative analyses of phagosomes from different species. In addition, this model provides a novel framework that can be used to understand the host-pathogen interaction and additional functions of this organelle. (Stuart et al, Nature 2007).
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