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Characterising protective local and systemic immune responses to Group A streptococcal throat infection in children

  • Full or part time

    Dr L B Nicholson
  • Application Deadline
    Monday, November 25, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The project:

Group A streptococcus (GAS) causes infective, invasive and post-infective immune-mediated diseases including serious heart and kidney conditions resulting in significant illness and 0.5-1.5 million deaths/year globally. This is greater than the deaths/year caused by malaria. Despite this, there is no vaccine available. Immune responses to GAS can be both protective and harmful (e.g. causing rheumatic fever). Immunity to GAS develops following natural infection and understanding both protective and harmful immune responses is key in the development of a safe and effective vaccine.

The commonest UK GAS disease is pharyngitis (‘strep throat’) in school-age children. This project will use established sampling protocols and state-of-the-art laboratory methods to characterise fundamental characteristics of the human immune response to this disease by studying how tonsillar and peripheral blood T and B-cells respond to candidate GAS vaccine antigens in children following GAS pharyngitis and recurrent tonsillitis. There are 3 objectives:
1. Describe the tonsillar (i.e. mucosal site-of-disease) immune responses to GAS vaccine antigens and compare these to circulating blood (samples from children undergoing tonsillectomy).
2. Describe the immune responses to GAS vaccine antigens in blood from children presenting with acute pharyngitis.
3. Use T-cell receptor (TCR) and B-cell receptor (BCR) profiling techniques to identify and quantify GAS-specific TCRs/BCRs to elucidate the T-cell/B-cell immune response to GAS and potentially identify public GAS-specific TCRs/BCRs (potentially effective vaccine targets).

Methods and Training – the student will join a thriving paediatric infectious disease unit and be trained in immunological and molecular techniques including cell culture, antigen stimulation, flow cytometry, cell sorting, microbial diagnostics and culture, qPCR and TCR/BCR sequencing, all of which are established in the laboratories of the main supervisors. GCP, statistics and bioinformatics training will be provided as well as collaborative experience with industry and other leading teams working on GAS in London and Melbourne.

Testing tonsils for GAS infection will involve learning qPCR and culture techniques, and interpreting results from blood tested for exposure to GAS. Immune responses following pharyngitis in patients who do or do not clear GAS in convalescence will be compared. Immune cells from blood and tonsils will be stimulated with GAS vaccine antigens (in collaboration with GlaxoSmithKline). The type and strength of GAS antigen-specific T and B-cell responses will be analysed by multiparameter flow cytometry, and cells will be separated by cell sorting for further analysis. GAS-specific immune cell populations will be processed for TCR/BCR sequencing and cutting edge bioinformatics approaches will be used to determine diversity, strength and specificity of GAS-specific T-cell/B-cell responses at different time points/in different clinical groups.

Necessary ethical approval achieved (Bristol Biobank).

This project addresses the urgent public health need for a better understanding of GAS specific immune responses, to facilitate the development of a safe and effective GAS vaccine. The laboratory and clinical environment of this translational project provides an energetic and supportive team, with a track record in achieving PhD success and publication. We welcome applications or informal enquiries.

Funding Notes

Funding: Medical Research Council GW4 BioMed Doctoral Training Partnership

How to apply: Visit MRC GW4 webpage: View Website Further project information available under the ‘Available projects’ tab, in the ‘Infection, Immunity and Repair Projects’ section.

Candidate requirements:
Essential: Interest in global health challenges, immunology and microbiology, First degree in biomedical sciences at class 2.1 or above obtained or about to be obtained. Applicants with a class 2.2 degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience. UK/EU residency. English language requirement.
Desirable: Experience in the laboratory, particularly microbiology and immunology.

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