The Role of the Staphyloccocal Ess in the modulation of host responses

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Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:Staphylococcus aureus is a bacterium responsible for a range of illnesses, but is most widely known as a cause of hospital acquired infections. These infections can be severe and difficult to treat due to the rise in antibiotic resistant strains of S. aureus, e.g. Methicillin Resistant S. aureus (MRSA). S. aureus is primarily thought to reside outside host cells during infection, but is now recognized to have an intracellular lifestyle. Bacteria residing within cells have been associated with persistent infections and evasion of antibiotics. It is thought that S. aureus manipulates host cells by the secretion of a wide range of toxins, as many bacteria do. For controlled export of the toxins into the host, bacteria require secretory machines in their cell membrane. S. aureus has a specialised secretion machine known as the Esat-6 secretion system (Ess). Similar Esat-6 systems were originally discovered in Mycobacterium tuberculosis, the pathogen that causes tuberculosis. The staphylococcal Ess proteins are important for bacterial virulence, and are currently being considered as vaccine candidates. Our recent work demonstrated that an Ess protein interferes with cell death during staphylococcal infection. However, the basic mechanisms underlying Ess-mediated modulation of human cell processes and persistent infections remain unclear. In this work, we will investigate the role of the Ess machine in the lifecycle and replication of S. aureus inside human macrophages, cells involved in host defence. We will assess the impact of the Ess system on macrophage cell signalling pathways and immune responses using a variety of molecular, cellular and high-resolution microscopy techniques. Moreover, as persistent infections are hard to study, we will develop sensitive techniques to model and visualise long term infections, using physics and engineering based approaches. Specialised human organ mimics will be developed in the laboratory to investigate the mechanism of action of the Ess proteins in S. aureus persistent infections in physiologically relevant conditions.