University of Dundee

MRC DTP 4 Year PhD Programme: Cell biology of a bacterial nano-weapon

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Supervisors: Dr Sarah Coulthurst (University of Dundee and Dr Colin Rickman (Heriot-Watt University)

Many bacterial pathogens use the Type VI secretion system (T6SS) nanomachine to fire diverse, toxic ‘effector’ proteins directly into target cells. It is becoming increasingly apparent that the T6SS plays a key role in the virulence and competitiveness of diverse Gram-negative bacteria, including important humanpathogens. Pathogens can use T6SSs to directly target eukaryotic organisms, as classical virulence factors. Alternatively, many pathogens can use T6SSs to target other bacterial cells, killing or inhibiting rivals. ‘Anti-bacterial’ T6SSs thus provide a competitive mechanism to allow pathogens to proliferate in polymicrobial infection sites or environmental reservoirs and ultimately cause disease.Understanding how the T6SS is deployed and the lethal consequences of its effectors on targeted bacterial cells therefore offers the potential to uncover new ways to kill or inhibit bacterial pathogens.This project aims to develop and utilise advanced fluorescence microscopy and image analysis methodologies to better understand how the T6SS is deployed and the consequences of specific effectors on targeted bacterial cells. In previous work, we have shown that the potent anti-bacterial T6SS of an opportunistic pathogen, Serratia marcescens, is deployed in an offensive manner and delivers multiple anti-bacterial toxins. Furthermore, we and others have shown that single cell microscopy approaches allow visualisation of the T6SS structure, firing events, and the subsequent impact on target cells. In this project, we will further investigate how the T6SS is deployed, using a combination of genetic, biochemical, high-and super-resolution microscopy and image analysis methods. Additionally we will elucidate the consequences of an individual T6SS-delivered anti-bacterial effector protein on the targeted bacterial cell, again by combining state-of-the-art single cell imaging with complementary genetic and molecular analyses.

Recent work from the lab can be found in the following references:

1.Mariano, G., Trunk, K., Williams, D.J., Monlezun, L., Strahl, H., Pitt, S.J. & Coulthurst, S.J.(2019). A new family of Type VI secretion system-delivered effector proteins displays ion-selective pore-forming activity. BioRxiv DOI 10.1101/676247

2.Trunk, K., Peltier, J., Liu, Y., Dill, B.D., Walker, L., Gow, N.A.R., Stark, M.J.R., Quinn, J., Strahl, H., Trost, M. & Coulthurst, S.J.(2018) The Type VI secretion system deploys anti-fungal effectors against microbial competitors. Nature Microbiology, 3, 920–931. PMCID: PMC6071859

3.Ostrowski, A., Cianfanelli, F.R., Porter, M., Mariano, G.,Peltier, J., Wong, J., Swedlow, J.R., Trost, M. and Coulthurst, S.J.(2018) Killing with proficiency: integrated post-translational regulation of an offensive Type VI secretion system. PLoS Pathogens, 14, e1007230. PMCID: PMC6082577