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PhD projects 2018

These are the PhD projects available to students joining the CMBI in October 2018. The links to the supervisors' webpages allow potential applicants to explore in further detail the research covered by each PI group.

Project TitlePrincipal Supervisor
Protective microbes: defining how the microbiota protects against AMR pathogen infection and transmission

Humans are home to approximately 100 trillion symbiotic bacteria (the commensal microbiota) which are critical for protecting us against infection. Our recent work (Brown et al, Nature Comms, 2017), has identified synthetic communities of commensal bacteria that protect against respiratory infection by antimicrobial resistant (AMR) pathogens. In this PhD project, we will investigate how the host senses these commensals, how this enhances innate immune protection against AMR pathogens, and determine whether these commensals can protect against the transmission of AMR pathogens between hosts. This project will pave the way for future therapeutic use of these defined communities of commensal bacteria as a completely novel way to combat AMR pathogen infection and spread. In addition it will provide cutting-edge training in the exciting and highly sought-after areas of the microbiota and bacterial pathogenesis.

Dr Tom Clarke

Manipulating cell trafficking by bacterial effector proteins

Many disease-causing bacteria inject proteins into an infected cell to manipulate the normal functioning of the cell. These bacterial proteins have often evolved unique mechanisms to interrupt specific cell pathways and we can utilise them to learn more about the function of the targeted pathways. This project will use a bacterial protein that has evolved to specifically interrupt a recycling pathway.

Dr Abigail Clements

Pathogenesis of Shigella sonnei

Shigella sonnei causes the majority of Shigella infections in developed countries and those undergoing economic improvements. It has been assumed to utilize the same pathogenic mechanisms as other Shigella species however recent evidence indicates novel virulence factors (eg. T6SS, CPS) contribute to its virulence. This project will characterize Shigella sonnei virulence through the interaction with host cells and persistence in the environment

Dr Abigail Clements

Structural determination of the Legionella type IV secretion system by cryo-electron microscopy

Legionella pneumophila, which is the causative agents of Legionnaires' disease, uses a specialized type IV secretion system (T4SS), to transport hundreds of virulence factors, termed effectors, into host cells. Some of the characterized translocated effectors play a role in hijacking host cellular pathways to establish the intracellular niche where the bacteria survive, replicate and ultimately cause disease.
The proposed PhD project aims to determine the molecular organization of the large double membrane-spanning T4SS using single particle cryo-electron microscopy (cryo-EM) and to elucidate the mechanism behind effector secretion. Only a view of the atomic details of the complete T4SS can help us in understanding: (i) why this secretion system possess unique structural features that are absent in other T4S systems? (ii) are these features connected with the diversity and quantity of secreted effector proteins? (iii) how is the T4SS gated? (iv) which is the substrate route within the secretion apparatus?
This project will allow not only to acquire expertise in the biochemical isolation and characterization of large membrane protein complexes, sample preparation for single particle cryo-EM, cryo-EM data collection and processing but also to understand the fundamental principles underlying the assembly of bacterial multi-protein complexes, define their structures and gain insight into their activities.

Dr Tiago Dias da Costa
The host genetics of intracellular bacterial infection

The Dionne laboratory works on innate immunity to bacterial infection, using the genetic and genomic tractability of Drosophila melanogaster to identify new molecular and physiological mechanisms of host defense. Our work is supported by grants from the Research Councils and by a Wellcome Trust Investigator award. We have identified a large number of Drosophila mutants with alterations in survival when infected with a broad-spectrum intracellular bacterial pathogen. In this project, the student will further characterise the immunological defects of one or more of these mutants. We will use Drosophila genetics, transcriptomics, and intravital imaging to explore the role of the implicated protein at the host-pathogen interface, thus identifying new molecular players in the interaction between host and bacterial pathogen.

Dr Marc Dionne

Understanding and overcoming antibiotic treatment failure

Antibiotic resistance poses an enormous threat to modern medicine and necessitates the use of less effective drugs, which can lead to relapsing or chronic infections. Work in our lab seeks to identify and characterise host and bacterial factors that modulate antibiotic efficacy. We then exploit this information to develop new approaches to improve treatment outcomes, either by using existing antibiotics in combination or by developing novel small molecule therapeutics.

Dr Andrew Edwards

A bacterial war game using the Type VI secretion System (T6SS)

The Type VI Secretion System (T6SS) is a contractile injection system, which is used by gram-negative bacteria to engage into a fight within the context of polymicrobial population. It produces a large range of T6SS toxins while protecting itself with cognate immunities. The fight results in controlling an appropriate population equilibrium within the community, by eliminating foes and cheaters. Our laboratory works with the bacterial pathogen Pseudomonas aeruginosa, a potent T6SS-carrying organism. We performed extensive work on the structure of the T6SS and in the characterization of the toxin-immunity couples. We developed strategies to manipulate the tip of the T6SS and could design T6SS tips loaded with selected set of toxins. We will engineer T6SS-modified strains and perform in vitro and in vivo competition using various combinations of attacker and prey cells. The overarching aim is thus to establish defined conditions to study the influence of the T6SS in polymicrobial populations and translate this knowledge in the development of super-hero strains that could protect from pathogens invasion.

Professor Alain Filloux

Impact of the Type VI secretion system (T6SS) in Pseudomonas aeruginosa CF isolates

Please note this project is available to Clinical Research Fellows only

Pseudomonas aeruginosa is a gram-negative pathogen systematically colonising the lungs and upper respiratory tracts of Cystic Fibrosis (CF) patients. The lung flora in young CF patients is usually polymicrobial, including other pathogens such as Staphylococcus and Burkholderia. Over the years, P. aeruginosa becomes prevalent and the main resident of the CF upper airways. Eradication using combined antibiotic therapies appeared not to be efficient and patients are undergoing course of relapse and exacerbations. This year WHO released a list of bacterial pathogens that need immediate attention because of AMR. P. aeruginosa has been ranked second and in the category critical that needs immediate attention. The strategies used by P. aeruginosa to prevail in the lungs and eliminate other bacteria is poorly understood, but two factors could be put forward. One is the ability to form biofilm which makes P. aeruginosa resistant to antibiotic treatment and immune eradication, the other is the use of a weapon to eliminate competitors in the lungs, namely the type VI secretion system (T6SS). The T6SS is a toxin injection device which is deadly for other gram-negative bacteria thriving in the same niche. Interestingly, T6SS and biofilm are co-regulated by a network that involves the second messenger c-di-GMP and quorum sensing. Different individuals with CF clearly demonstrate varying rates of disease progression. This may relate to host factors (e.g. modifier genes), environmental exposure or features of specific infecting pathogens but the contribution of each of these is currently poorly understood.

Professor Alain Filloux and Professor Jane Davies

Multidrug resistant Klebsiella pneumoniae infection

Please note this project is available to Clinical Research Fellows only

Klebsiella pneumoniae is an established human pathogen typically affecting hospitalised patients although an invasive community-acquired disease is also emerging in the far east. The rapid emergence of carbapenemase producing strains is the latest wave antimicrobial resistance mechanism amongst gram-negative bacteria. In the United Kingdom, Klebsiella pneumoniae is now the most prevalent carbapenemase producing invasive isolate detected from patients. This project will characterise large epidemic resistance plasmids in Klebsiella and their impact of virulence and persistence in mice to help understand the proliferation and spread of these resistance determinants.

Professor Gad Frankel and Dr Abigail Clements

Investigation of the physiological function of the signalling nucleotide c-di-AMP in the human pathogen Staphylococcus aureus.

Staphylococcus aureus can cause infections ranging from skin infections to endocarditis and bacteremia. Nucleotide signalling molecules have critical functions allowing bacterium to rapidly adapt to changing conditions, such as the transition from the environment to a human host. The nucleotide signalling molecule c-di-AMP is intimately linked to osmotic regulation and essential for the growth of S. aureus under standard conditions. However, the molecular mechanisms behind this are currently not understood. Key research questions that are addressed in the Gründling lab are: how c-di-AMP contributes to the regulation of the osmotic pressure in bacteria, how this affects their ability to cope with cell wall-targeting antibiotics as well as how fundamental processes such as osmolyte uptake and amino acid utilization are altered under low oxygen conditions, which S. aureus encounters during infection

Professor Angelika Gründling

Deciphering the roles of cAMP-dependent amino-acid transporters during Mycobacterium tuberculosis adaptive response at the molecular and physiological levels

The second messenger cAMP is one of the most widely used second messengers and key modulator of bacterial physiology. It regulates a wide variety of processes ranging from carbon metabolism to virulence. It is known that cAMP mediates its regulatory effects through allosteric interactions with cAMP-binding proteins, which then undergo conformational changes altering their activity. The M. tuberculosis genome H37Rv reveals ten putative proteins that harbour a cAMP-binding domain, including amino-acid transporters and efflux pumps. Characterisation of those is essential for the rational design of drugs to neutralise or interfere with these bacterial adaptions, potentially reducing or preventing antibiotic resistance.

Dr Gerald Larrouy-Maumus and Professor Thomas Meier

Synthetic antimicrobial peptides in the treatment of drug resistant bacteria

Cationic antimicrobial peptides (AMPs) are promising compounds with broad-spectrum activity against bacteria. We have designed short synthetic AMPs capable of killing drug-susceptible and multi-drug resistant Mycobacterium tuberculosis. The project will cover areas including 1) Non-tuberculous mycobacteria, such as M. abscessus and M. avium, which cause pulmonary infection, are intrinsically drug resistant, and produce biofilms. Treatment with conventional antibiotics is difficult and AMPs have the potential to disperse/prevent biofilm formation, and show synergism with antibiotics. 2) We have AMPs that kill M. tuberculosis, and we need to establish to what extent there may be synergy with 1st line anti-mycobacterial drugs. We will also investigate the mode of action on bacterial cells using imaging, and establish how AMPs get inside macrophages and target intracellular mycobacteria. The wax moth Galleria mellonella is available as an in vivo model to assess infection and treatment.

Dr Brian Robertson and Dr Sandra Newton

Inflammasome signalling in Tuberculosis: new routes to host directed therapy

Host directed therapy (HDT) augments the immune response to drive pathogen clearance and lessen the tissue damage associated with chronic infections such as Tuberculosis. The inflammasome is a multimeric protein comprised of intracellular sensor, adaptor, and pro-caspase-1; its assembly leads to processing of the pro-inflammatory cytokine, IL-1beta. Clinical isolates of M. tuberculosis show differential ability to activate the inflammasome and induce IL-1beta processing, and we have shown this can happen in the absence of inflammasome components that what were previously thought of as critical sensors. Pharmacological blockade of the inflammasome elicits both anti-inflammatory and anti-microbial activity, and can be used in combination with rifampicin.

This project will investigate the mechanism of alternative signalling, and establish the components involved in what may constitute a novel inflammasome. Other chemical blockades will be evaluated and synergistic effects with current anti-mycobacterial drugs investigated to devise an alternate regimen to test in vitro and in vivo. The project will cover a range of aspects of molecular biology, immunology and bacteriology, as well as tissue culture and in vivo models such as the wax moth Galleria mellonella. 

Dr Brian Robertson and Dr Avinash Shenoy

Anti-bacterial host-defence via inflammasomes

Mammalian inflammatory caspases (e.g. human caspase-1, 4, 5) have indispensable roles in immunity to infection. These caspases regulate cytokine processing, inflammation and tissue repair, and remove pathogen-niches by triggering pyroptotic death of infected cells. My group investigates mechanisms of caspase-mediated immunity to enteric pathogens such as Salmonella, E. coli and Listeria monocytogenes. We are broadly interested in answering: (i) how are caspases activated during infection and whether bacteria subvert these processes? and (ii) what is the molecular effector machinery mobilized by caspases to promote host defence? Exciting recent work identified new bacterial molecules that modulate caspase activity and the host response. In addition, a proteomic screen identified previously unknown substrates of caspase-1 which we believe have important immune functions. Based on their interest, candidates are welcome to develop a project addressing these questions.

Dr Avinash Shenoy

Mechanisms of survival and host(ile) takeovers of non-growing bacteria

Bacterial growth is often limited by availability of nutrients and most bacteria spend the majority of their time in prolonged states of very low metabolic activity and little or no growth. These non-growing states (NGS) are far less studied than other growth states. Although our knowledge of how bacteria enter the NGS has advanced in the past decade, our understanding of the factors that control metabolism in bacteria whilst in the NGS remains in its infancy. Further, bacterial viruses (phages) represent the most abundant living entities on the planet and most research on phage biology has been done in the context of growing bacteria. In Nature, however, phages largely encounter bacteria in the NGS and our knowledge of the mechanisms used by phages to successfully infect bacteria in the NGS remains elusive. The proposed PhD project will focus on mechanisms that (1) underpin how metabolism is regulated in the NGS and/or (2) allow phages to successfully infect non-growing bacteria. Since many bacteria in the NGS become refractory to diverse biotic and abiotic stresses, including antibiotics, the long-term expectation of this research is that a better understanding of how metabolism in the NGS is regulated and the strategies used by phages to infect bacteria in the NGS could inspire and inform truly novel and rational approaches to treat bacterial infections

Professor Ramesh Wigneshweraraj
PhD Example Projects