The Role of the Staphyloccocal Ess in the modulation of host responses
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
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.
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.
Organisations
People |
ORCID iD |
| Meera Unnikrishnan (Primary Supervisor) | |
| Kate Watkins (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N014294/1 | 30/09/2016 | 29/09/2025 | |||
| 1789104 | Studentship | MR/N014294/1 | 02/10/2016 | 30/03/2021 | Kate Watkins |
| Description | School Visit (Leamington Spa) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | I was involved in running a workshop for children in year 4 (8-9 year olds) at St Margarets school Leamington on the 22nd June 2018. The aim of the session was to introduce the students to microbiology with an emphasis on hygiene and how bacteria is cultured in the lab. An experiment was set up that involved 3 classes of year 4 children (roughly 90 children). The activity involved the collection of the microbes from each students hand after they had either washed their hands with soap, washed their hands with water only or not washed at all. A short verbal introduction was given to the class followed by the hand washing/not washing and finally the collection of microbes via the student carefully pressing fingers on an agar plate and labelling with their name. The plates were taken back to our lab to allow the microbes to grow then photographs were taken of each agar plate. I made a powerpoint presentation that included all of the photographs and information about the impact of washing hands and how useful experiments are. This was sent to the school for the teachers to present and discuss with the students. |
| Year(s) Of Engagement Activity | 2018 |
| Description | School visit (Coventry) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | The whole of the second year at the Bablake school Coventry attended a workshop that I helped to run along with 7 other student/member of Staff from Warwick University. The workshop was about bacteria transmission and the formation of biofilms. • Hands on Activity - in groups of 6 (each form had approximately 4 groups). • Glo-germ gel/powder will be placed on objects they will handle (without them knowing). Glo germ can be easily visualised by UV light and is safe. Also showed transmission through shaking hands. • Each group built bacterium models with modelling clay. UV light will be shined on their hands to show them how the germs have spread from the models (need to darken room for this). If time permits, to demonstrate transmission, Glogerm gel will be applied to hands of some group members and they will shake hands with other group members. • Pupils can washed their hands and then saw how many 'germs' were left. After this pupils can stamped their finger onto a LB plate, and it was taken back to culture in the University labs. Photographs of the plates were sent a couple of days after so that the pupils saw what they had on their hands. |
| Year(s) Of Engagement Activity | 2019 |
| Description | UK Cellular Microbiology Network Conference 2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | I presented my research findings in a 15 min oral talk to an audience of postgraduate students, post docs and PIs |
| Year(s) Of Engagement Activity | 2019 |