This 30 credit module covers the broad area of infectious disease, taking advantage of active research taking place at St George’s by exploring some of the specific causes of infection such as tuberculosis, malaria, MRSA and viral infections such as HIV. You will learn about the cellular and molecular responses to infection, including innate and adoptive immune responses, and responses that are deleterious.
The module provides insight into the pathogenesis of infection and the virulence mechanisms involved. It also demonstrates how an understanding of these processes drives vaccine development, antibiotic treatment and immunotherapy. You will learn how new sequencing technologies and ‘omics’ methodologies are providing novel insights into the human microbiota, susceptibility to infection, tracking of infectious disease, and mechanisms underlying resistance to antibiotics.
The substantive research project is worth 105 credits. Here are some examples of past student projects:
Bioinfomatic approaches to meta-data analysis of drugs and drug targets
Aims: Understand how NF-kB signalling is inhibited during human cytomegalovirus replication.
Brief overview: Human cytomegalovirus is major human pathogen affecting both immunocompetent and immunodeficient patient populations. We and others have discovered that the NF-kB inflammatory signalling pathway is important for HCMV replication. Moreover, we have discovered a novel mechanism by which we believe HCMV antagonizes NF-kB signalling. Therefore, we will investigate antagonism of NF-kB signalling in HCMV infected cells. The Strang laboratory is an open, welcoming, multi-disciplinary environment. As in previous years, motivated students who work to high standards may see their work published in high quality professional journals.
Methods used for data collection: Standard molecular and cellular techniques for protein and gene expression analysis. Chemical biology and chemical genetics.
Lung-targeted vaccination for tuberculosis
Background: Tuberculosis (TB) is a global health problem, affecting millions of people worldwide. One-third of the world’s population is estimated to be latently infected with M. tuberculosis, and approximately 5–10 per cent of exposed individuals are expected to develop TB. Improved control measures at many different levels, including a more effective vaccination approach, are urgently needed to combat the world-wide spread of the TB epidemic. New vaccination approaches have been proposed, either as a replacement for the BCG vaccine, or as a boost to it, and a number of those are in clinical trials. In the meantime, further studies are needed, in order to provide the next generation of TB vaccine candidates for future clinical trials.
Aims: To test the vaccine potential in mice of a novel vaccine candidate against tuberculosis, which showed promise in our preliminary studies.
The new vaccine approach relies on lung heparin targeting and nanoparticles for antigen delivery. We used the heparin-binding hemaglutinin adhesion (HBHA) protein of M. tuberculosis fused to the protective Ag85B to coat the surface of NaMA nanoparticles (Particle Sciences Inc) in order to generate the ‘NanoAH’ vaccine. Thus we have already shown that using this strategy, immune responses can be induced locally (in the lungs) and systemically (in the blood) and that the induced immune response resulted in reduction of the TB infection in mice superior to that conferred by the current TB vaccine (BCG) alone. However, the one difficulty of this approach is that the Ag85B-HBHA (AH) protein is difficult to generate in soluble form in E. coli. Therefore, we generated a truncated version of HBHA that still retains heparin-binding capacity but is smaller in size and easily generated.
The aim of this project is to test whether the truncated version of HBHA could be used to replace the full-length protein without affecting the efficacy of the NanoAH vaccine. The new version of the vaccine is termed NanoAHC.
Methods used for data collection:
- quality control of the AHC fusion protein (by SDS-PAGE and Western), which has already been generated in the lab, and additional purification if required
- immunisation of mice intranasally
- immunological assays (antibody measurement in serum, analysis of sIgA in lung lavage, proliferative cellular responses using spleen cells)
- infection of mice with MTB (the student will only be an observer)
- bacteriological assays
- statistical evaluation of data using GraphPad Statmate 2 software
Inflammatory mediator production resulting from interactions between house dust mite allergens and stimulation of virus pattern-recognition receptors
Aims: To investigate the relationship between ROS production and inflammatory mediator upregulation in airway epithelial cells following exposure to allergens and virus surrogates.
Brief overview: We have discovered that the major house dust mite allergen called Der p 1, which is a cysteine peptidase, unexpectedly activates a signalling pathway which converges with the production of reactive oxidants (ROS) triggered when virus pattern recognition receptors (TLR3, MDA5, RIG-I) are stimulated. There is considerable interest in this mechanism because of its potential relevance to the triggering of asthma exacerbations. Transcription factors which promote the expression of cytokines responsible for the development and maintenance of allergy are redox sensitive, and many people with asthma have impaired antioxidant defences, leading to oxidative stress and increased gene expression. As a key step in exploring this interaction between allergen- and virus-dependent signalling we now wish to establish which mediators are upregulated.
Methods used for data collection techniques: General cell and molecular biological approaches, Click chemistry, quantitative protein determination, ELISA/chemiluminescent assay, fluorescent antibody labelling, fluorescent intracellular probe labelling, and reaction kinetics.
Identification of glucose transporters in the airway epithelium and their role in glucose homeostasis
Aims: To further identify glucose transporter isoforms in the airway and distal lung epithelium and characterise their transport function.
Brief overview: We have identified some glucose transporters that are important for glucose homeostasis across the airway epithelium (GLUT1, 2 and 10). However, a number of other isoforms that have been identified by transcriptomic screening may also have important function. This project will investigate the expression of GLUT and SGLT mRNA in primary airway cells and tissue from mice and humans. The abundance and localisation of key isoforms will be investigated using protein biochemistry and histological techniques. The function of these transporters and their role in glucose homeostasis across the lung epithelium will also be investigated using glucose transport assays. The identification of functionally important glucose transporters will be aided by the use of mice in which GLUT isoforms (1,2,5 and 10) and SGLT1 have been genetically knocked out.
Methods used for data collection: Mouse and human airway cell culture, PCR, western blot, immunohistochemistry, glucose flux measurement.