Regulation of neutrophil functions by cell cycle proteins

Neutrophils are the most common immune cells circulating in the blood stream; they account for 50-70% of all white blood cells and are essential for defending us from bacteria, viruses and other parasites. They are found in all vertebrates, including fish, birds and mammals, and are the 'first-responders' to infections and wounding - they move rapidly into the affected tissues to deal with the microbial threat. If neutrophils do not arrive to the correct place, or if they arrive too late, the body remains defenceless. Once they have located the invaders, neutrophils have several ways of destroying them to prevent the infection from spreading. They can engulf microbes and kill them by producing toxic chemicals such as bleach. Neutrophils can also release "NETs" - Neutrophil Extracellular Traps. NETs are made when neutrophils release webs of DNA that are adhesive and contain toxic antimicrobial proteins; NETs trap microbes and prevent them from spreading. The toxic antimicrobials that neutrophils use against microbes are a dangerous cargo. Their release via NETs must be carefully controlled because they also have the potential to damage our own cells and tissues. In fact, neutrophils are often incorrectly activated in many non-infectious diseases. These include various autoimmune diseases, such as lupus, rheumatoid arthritis and asthma, but also cancer and atherosclerosis (which leads to stroke or heart attack). Despite their relevance for disease, we know very little about how neutrophils 'decide' to react one way or another. The aim of this Fellowship is to understand which genes control neutrophil behaviour and how signals from the environment regulate the way in which a neutrophil acts. I found that genes which normally control cell division are also involved in regulating neutrophil functions. This is an exciting hypothesis because it would give us a major insight into how neutrophils carry out their tasks and how things go awry. Since cell division genes are extensively studied in the context of cancer, it might also mean that certain cancer drugs could be re-purposed to treat diseases where neutrophils show faulty behaviour. The research outlined in this MRC CDA Fellowship is interdisciplinary and combines concepts from different areas of biology (immunology, cell division and microbiology). The University of Bristol will be an ideal place to be immersed with researchers from all of these fields, and to have access to unique technical expertise, all of which will be invaluable throughout my Fellowship.