Identifying Defects in Innate Immunity in Patients with Diabetes on a Cellular and Molecular Level

This project is offered as part of the Medical Research Foundation National PhD Training Programme in AMR: https://www.findaphd.com/search/PhDDetails.aspx?CAID=3755

Staphylococcus aureus is a major cause of morbidity and mortality in elderly patients with diabetes. S. aureus is the most frequent pathogen isolated from diabetic foot ulcers and patients are at a significant risk of life-threatening S. aureus bacteremia, with evidence that MRSA is a particular problem in disseminated infections complicating foot ulcers. Phagocytes including neutrophils and monocytes provide critical cellular defences against S. aureus, and studies indicate that the immune functions of neutrophils from diabetics are defective. This is compounded by profound immunological changes in the ageing population. Our objective is to identify pathways in which phagocytes isolated from diabetics fail to kill S. aureus, in order to define novel therapeutic targets to promote immunity in patients with diabetes. Such strategies will improve S. aureus killing of both resistant and sensitive strains by the host and thus reduce requirements for extended antibiotic treatment and the risk of highly resistant strains emerging. Phagocytes will be isolated from people with diabetes and age-matched healthy controls will be subjected to in vitro assays of immune function against S. aureus (inc. phagocytosis and bacterial killing). Molecular interactions with S. aureus and molecules involved in bacterial killing (including endogenous antimicrobials and redox molecules) will be visualised by super resolution microscopy. We aim to reverse phagocyte defect(s) and enhance antibiotic-dependent and antibiotic independent pathogen killing ex vivo with candidate inhibitors including statins and macrolides, as well as inhibitors of PI3k, which are predicted to play key roles in phagocytosis and other immune processes. Other targets/compounds that are identified as part of parallel SHIELD projects will also be screened. You will receive training in basic science disciplines of leukocyte biology and super-resolution microscopy to develop new ways of studying phagocytosis and killing of pathogens, receive training in research governance and gain clinical exposure by attending diabetic clinics. The successful candidate will also be embedded in the MRC Discovery Medicine North (DiMeN) DTP for additional training opportunities and local cohort activities

Apply here: https://www.sheffield.ac.uk/postgraduate/research/apply

When you complete the online application you need to choose: Department of Infection, Immunity and Cardiovascular Disease under the ‘Department’ section and Sabroe/Cadby as your preferred supervisors. In the funding section please select 'Other organisation' as your funding source and in the box below that where is asks for details of your funding source please put Medical Research Foundation National PhD Training Programme in AMR Research. Please also ensure that you put your project title in the research topic section.