Studies into the physiological reactions of myeloperoxidase (MPO) within the neutrophil phagocytic vacuole

Bacterial and fungal infections are a major cause of human and animal morbidity and mortality. If we understand the way in which the body normally deals with these infections we might be able to enhance these mechanisms, particularly important as antibiotic resistant microbes are emerging in increasing numbers. In addition, as the systems that are toxic to microbes can also damage normal tissues, this understanding can also be used to limit damaging inflammatory diseases such as arthritis. The most important cells involved in protecting the body against these infection are the neutrophils, the most numerous of the white blood cells. A key question is whether the enzyme myeloperoxidase acts to generate a toxic molecule, hypochlorous acid which is present in bleach, or to remove hydrogen peroxide from within the leukocyte. We will combine our expertise in different scientific disciplines to answer this fundamental question.

Neutrophils provide the primary effector system of the innate immune system. They ingest bacteria and fungi which they kill and digest. The killing process is associated with the generation of H2O2 within the phagocytic vacuole which is thought to act as substrate for MPO mediated halogenation of the organism. The possible reactions between H2O2 and MPO have been mathematically modelled and produced in the test-tube. By combining our expertise in neutrophil biology and bioenergetis, we propose to measure the reactions that actually occur within the phagocytic vacuole. This is essential to understanding the role of MPO and the mechanisms by which microbes are killed.