The role of PtdIns3P in the killing of bacteria and fungi by the neutrophil NADPH oxidase

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Neutrophils are white blood cells in our body which are responsible for finding, eating and killing nasty microbes. An important part of the killing process is the delivery of large quantities of toxic oxygen molecules into a specialist chamber inside the neutrophil called a phagosome, which contains the microbe. These toxic chemicals are made by an enzyme called the NADPH oxidase and we know it must be important because of the discovery of a rare disease called CGD (chronic granulomatous disease), where patients carrying mutations in one of the six proteins which make up this enzyme suffer life-threatening bacterial and fungal infections. The way in which the NADPH oxidase is turned on is complicated, because it has to switch on in response to eating a wide variety of different microbes but at the same time it mustn?t cause too much damage to surrounding body tissues. An understanding of how the NADPH oxidase works is thus likely to improve our understanding of what goes wrong when some infections and inflammations are not dealt with properly. The applicants have recently discovered that enzymes called PI3Ks may play a key role in regulating the NADPH oxidase by synthesising a messenger molecule around the phagosome called PtdIns3P, which they have shown binds tightly to one of the six NADPH oxidase components. They propose to use chemicals recently developed by the pharmaceutical industry to specifically block PI3Ks to assess their role in the synthesis of PtdIns3P and NADPH oxidase function. Most of these experiments will be done on neutrophils purified from human blood taken from local volunteers. The applicants have also created mutant mice in which the gene encoding the expression of the oxidase component which binds PtdIns3P has been altered to prevent this interaction. These mice are healthy and fertile when housed under pathogen-free conditions and they now propose to evaluate the effect of this mutation on the ability of these mice to combat bacterial and fungal infections; most of the experiments will be done on neutrophils purified from the bone marrow of these animals. This group has a strong track record in publishing their work in the public domain and are regularly asked to present their work at international conferences. They have also developed good links with the pharmaceutical industry and hence useful results from the work should be quickly disseminated.