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PhD projects 2019

These are the PhD projects available to students joining the CMBI in October 2019. The links to the supervisors' webpages allow potential applicants to explore in further detail the research covered by each PI group.

Project TitlePrincipal Supervisor

Antibiotic resistance and novel therapeutic approaches

Work in my lab is focused on determining how antibiotics and host immune defences kill bacteria and the strategies used by pathogens to tolerate or resist these threats. We then exploit these findings to identify targets for novel therapeutic approaches, in collaboration with industrial partners and colleagues from the Department of Chemistry. This project will focus on the mechanisms by which Staphylococcus aureus repairs damage caused by antibiotics, which can lead to the acquisition of tolerance or resistance.

Dr Andrew Edwards

Multi-Omics approaches to decipher the role of Albumin on Tuberculosis pathogenesis

Albumin is the most abundant protein in human blood plasma with approximately 35-50 g/L of serum. However, its impact on Mycobacterium tuberculosis physiology has not been the subject of in-depth investigation. Preliminary data from the lab have shown that levels of albumin have a drastic impact on M. tuberculosis metabolism. In this PhD, by using integrated multi-Omics approaches (metabolomics/proteomics), the student will determine the role of albumin on M. tuberculosis physiology aiming to identify key metabolic pathways and enzymes important for Mtb adaptation in order to preclude the dissemination of M. tuberculosis.

Dr Gerald Larrouy-Maumus

Caspases and Inflammasomes in Innate Immunity

Inflammasomes mediate innate immunity to infection and trigger inflammation in hereditary syndromes by activating caspase-1. My group investigates (i) the mechanisms of activation of inflammasomes, (ii) the effector programmes orchestrated by caspases, and (iii) subversion of caspases by pathogens (ref 1-4). Many cellular and systemic effects of inflammasomes are brought about by poorly characterised substrates of caspase-1. We have been identifying and characterising new substrates of human caspases (ref 5). For example, we discovered UBE2L3 as a caspase-1 target, and the autophagy protein p62/SQSTM1 as a substrate of caspase-8 (ref 6). We are also interested in how bacteria subvert these pathways. For instance, we found that pathogenic E. coli inhibit caspase-4 in the gut (7). In this PhD project, the candidate will benefit from our open, collaborative and multidisciplinary approach to investigate the immune roles of exciting new candidate genes. I also have a Satellite Laboratory at The Francis Crick Institute, London where the candidate could network and access specialised facilities as and when necessary. Our funding sources include the MRC, Wellcome Trust, EPSRC and the Royal Society.

Dr Avinash Shenoy 

The host as a selective pressure: interactions of immunity, AMR, and persistence

The Dionne laboratory studies the interaction of bacteria with the fruit fly Drosophila melanogaster; this allows us to identify fundamental mechanisms of immunity and of interaction of microbial pathogens with the host. The goal of this project is to understand how the selection imposed by host immune responses changes bacterial biology. We will infect fruit flies with relatively mild bacterial pathogens and track phenotypic and genotypic change in infecting bacteria. We will compare bacteria evolved in wild-type hosts to those evolved in hosts lacking specific aspects of immune function. We will then cross-correlate the changes we observe in pathogenic activity with changes in other related phenotypes (persister formation, antimicrobial resistance) to develop an understanding of how the interaction with non-human hosts can change fundamental aspects of microbial biology. This is of particular interest given the strong reliance of insect immune responses on antimicrobial peptides and the potential for cross-resistance between antimicrobial peptides and other drugs of interest.

Dr Marc Dionne

Unravelling the molecular mechanisms behind the emergence of Shigella sonnei

The Shigella species flexneri and sonnei cause approximately 90% of bacterial dysentery worldwide. While S. flexneri is the dominant species in low-income countries, S. sonnei causes the majority of infections in middle and high-income countries1. While closely related genetically it is becoming clear that these two species have significant differences in their pathogenic determinants. Foremost are the variety of saccharide layers that present as the external face of the bacteria. S. sonnei has a unique O-Antigen that is presented on the bacterial cell surface in two forms: attached to the lipid-A:core to form a traditional lipopolysaccharide and to an unknown anchor as a group 4 capsule2. Additional surface polysaccharides are also present in S. sonnei. This project will investigate how these surface polysaccharides contribute to S. sonnei virulence and modulate the host response, as well as their contribution to survival of the bacterium outside the human host. A combination of genetic, biochemical and cell biology approaches will be used to address these questions.

Dr Abigail Clements

Using transposon mutagenesis and high throughput next generation sequencing to identify Staphylococcus aureus genes essential for acid stress survival.

Hospital-acquired infections with methicillin resistant Staphylococcus aureus (MRSA) strains are a leading cause of illness and death and impose a large economic cost on patients and hospitals. MRSA stains have now also emerged as important community pathogens causing infection in previously healthy individuals with no recognizable risk factors. Novel classes of antibiotics and more effective ways of treating such infections are needed. Genes essential for the growth and stress resistance of S. aureus are currently explored for their value as novel drug targets. As part of this work, we aim to identify and subsequently characterize genes that are essential for acid stress resistance in S. aureus.

Our recent work has shown that the signalling molecule c-di-AMP contributes to acids stress resistance in Staphylococcus aureus. Specifically, we have shown that a strain producing high levels of c-di-AMP has increased while a strain with low levels of c-di-AMP has decreased acid stress resistance as well as beta-lactam antibiotic resistance. However, the mechanism by which c-di-AMP contributes to acid stress resistance as well as beta-lactam antibiotic resistance is not known and will be further investigated. As part of this project, the contribution of Urease and other known acid stress resistance genes will be assessed in S. aureus and test if their function is altered in high- or low-level producing c-di-AMP strain. If differences are observed, the mechanism behind this will be further investigated. In addition, we will perform a global, genome-wide screen to identify novel genes required for acid stress resistance in S. aureus. To identify such genes, a transposon mutagenesis and high throughput sequencing (Tn-Seq) experiments will be performed using a wild-typeMRSAstrain as well as strains producing altered c-di-AMP levels and exposing the strains to different acid stress conditions. Using this approach, it should be possible to identify novel genes required for general acid stress resistance in S. aureus as well as genes that are specifically required in strains with altered c-di-AMP levels. The function of the proteins encoded by such genes will be further investigated also in terms of their requirement for antibiotic resistance in S. aureus.

Professor Angelika Grundling 

Understanding and exploiting Group A streptococcal anti-chemotactic proteases in medicine

Streptococcus pyogenes (Group A streptococcus; GAS) is an important human pathogen responsible for a significant global disease burden of mild to life-threatening infections, with no effective vaccine and increasing reports of antibiotic resistance. Streptococcus pyogenes produces two conserved cell envelope proteinases that co-ordinately abrogate the activity of the two major neutrophil chemotactic signalling families. SpyCEP (S. pyogenes cell envelope proteinase, encoded by cepA) cleaves and inactivates the entire family of CXC chemokines that ligate neutrophil CXCR1 and CXCR2 receptors and C5a peptidase (encoded by scpA) cleaves and inactivates the potent anaphylatoxin and chemotactic agent C5a, and also C3a.  With a dual role as adhesin, scpA plays a pathogenetic role in early streptococcal infection, while SpyCEP plays a key role during late and more invasive infection. Taken together, the two enzymes provide a sustainable system to prevent host neutrophil recruitment throughout the infection process.  SpyCEP and C5a peptidase are both leading non-M protein S. pyogenes vaccine targets, with proven activity in a number of animal models. Current models are in sufficient to define their precise mechanism of action. This information is key to a deeper understanding of the role anti-chemotactic proteases play in GAS host immune evasion and could provide an essential stepping stone for vaccine development. In a recent pilot study, we applied our combined experience working with bacterial surface proteins, bespoke production methods, NMR spectroscopy and the new VMXi beamline at Diamond Light Source. We have successfully identified new crystal forms of SpyCEP for diffraction and obtained encouraging in-solution structural data on the protease-substrate complexes. In this project we complete a comprehensive structural characterisation of SpyCEP and C5a peptidases and supplements this with enzyme kinetics, substrate binding specificities and cell biology assays. Using our structural and biochemical insights, we will identify regions in SpyCEP and C5a peptidases that could be grafted into a unified antigen target that would provide the starting point for the development of a novel vaccine.

Professor Steve Matthews & Professor Shiranee Sriskandan

Mechanism by which the Salmonella protein SteD reduces MHCII from the surface of antigen-presenting cells

Major Histocompatibility Complex Class II (MHCII)-dependent antigen presentation to T-cells by dendritic cells (DCs) is important for induction of adaptive immunity to intracellular bacteria. Salmonella enterica causes gastroenteritis and typhoid fever. DCs infected by Salmonella undergo a dramatic decrease of cell-surface MHCII, thereby decreasing their ability to activate T-cells. The Salmonella virulence protein SteD is required and sufficient for this process. SteD induces MHCII ubiquitination, leading to its lysosomal degradation.

We have recently identified two host proteins required for SteD-dependent MHCII surface level decrease, and the aim of this project is to use methods of molecular cell biology to understand how SteD uses them to decrease cell surface MHCII.

Professor David HoldenProfessor Shiranee Sriskandan
   
   
   
   
PhD Example Projects