Role of Rho-family GTP-binding proteins in mammalian phagocytosis -a siRNA approach

It is essential for an organism to get rid of dead cells and invading microorganisms. Specialized cells of the immune system, called macrophages, are particularly equipped for clearance of particulate material, a process referred to as phagocytosis. Anomalies in recognition or uptake result in inflammatory diseases and life-threatening infections. We need to better understand the fundamental mechanisms of phagocytosis to help design new drugs for patients suffering from these diseases. To do so, our research will focus on a particular class of molecules that control phagocytosis. We will determine which of them control uptake of different types of particles, and how they are regulated to do so. Thereby, it will later be possible to design drugs that block the adverse effects of phagocytosis, whilst maintaining of even boosting (where necessary) the beneficial sides of this fundamental physiological process.

Evidence from mammalian and Drosophila indicate the existence of several modes of phagocytosis, controlled by distinct Rho-family members. Rho proteins are activated by phagocytic receptors and during bacterial invasion; they are recruited to the site of uptake where they control cytosketal remodelling and particle internalization. We will use RNA interference to determine in an unbiased fashion which Rho-family members control opsono-phagocytosis of model particles and bacteria. Subsequently, we will precise the mechanism of their regulation. These experiments will provide the first comprehensive analysis of the contribution of these signalling molecules to mammalian phagocytosis. In the long term, by defining how many modes of uptake co-exist in phagocytes, our work will allow the rational design of drugs able to block or boost uptake without impairing other essential functions associated to phagocytosis, such as bactericidal activity, transcriptional activation, antigen processing and presentation.