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GW4 BioMed MRC DTP PhD studentship - Escaping host immunity: Defining Staphylococcus aureus complement evasion mechanisms


Department of Biology & Biochemistry

About the Project

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 17 studentships for entry in October 2021. More information about the DTP may be found here: https://www.gw4biomed.ac.uk/.

SUPERVISORY TEAM:

Dr Maisem Laabei (lead), University of Bath, Department of Biology & Biochemistry https://researchportal.bath.ac.uk/en/persons/maisem-laabei
Prof Ruth Massey, University of Bristol
Dr Mario Recker, University of Exeter
Prof Jean Van Den Elsen, University of Bath

THE PROJECT:

Background:

Staphylococcus aureus is a major human pathogen that causes a broad range of infections resulting in significant morbidity and mortality globally. Due to the constant threat of antimicrobial resistance, the WHO has placed S aureus on the list of priority pathogens for which the development of antibiotics and novel immunotherapeutics is urgently required. To effectively develop anti-infective therapies to combat S aureus infection, a greater understanding of the virulence mechanisms promoting disease is required. All successful pathogens have evolved mechanisms to resist host immunity which are intimately aligned with their pathogenicity. Importantly, the primary host response to S aureus occurs via complement. Complement is an elegant evolutionarily conserved system, playing essential roles in early defences by working in concert with immune cells to survey, label and destroy microbial intruders and coordinate inflammation. Dissecting how this bacterial pathogen escapes complement detection is the overall goal of this project.

Aims and overview:

This project will employ gold standard molecular biology tools and multi-omic approaches to determine both the essential mechanisms of complement resistance and the genetic regulatory elements that underpin their expression. In tandem, by combining genomic, phenotypic and previously collected clinical data this study will develop machine learning frameworks to discover associations between the immune evasiveness of clinical isolates and their ability to cause severe infection. Previous work indicates that S aureus is a master of complement evasion. Based on antibody responses to S aureus infection, we hypothesize that there is a hierarchy of effective complement strategies where evasins are expressed in response to local environmental cues.

Objective 1: To test this hypothesis, we will examine the individual role of cell wall anchored proteins and assess their contribution to protection against complement under different environmental conditions aimed at mimicking in vivo infection. Here the student will create isogenic mutants of key cell wall proteins and develop a novel complement deposition assay providing a high-throughput readout for complement evasion. How immune evasion molecules are regulated both under lab conditions and those mimicking in vivo infections remains a mystery and will be explored in this objective. We hypothesis that increasing exposure to serum components and limitation of important nutrients triggers an upregulation of evasive mechanisms that occurs via global virulence regulatory systems.

Objective 2: Here we will use cutting-edge transcriptomic analysis by employing high resolution RNA sequencing to determine differential gene expression under lab and in vivo like conditions. These environmental specific global gene expression profiles will be used to reveal the regulatory framework responsible for complement resistance in S aureus. Lastly, we will examine complement evasion in a cohort of clinically relevant, genetically diverse genome sequenced S aureus isolates.

Objective 3 will employ a functional genomics approach, combining genotype and phenotype, enabling genome-wide association studies (GWAS) to identify genetic signatures associated with increased or decreased immune evasiveness. These signatures will be further tested and functionally confirmed in the lab, revealing novel genes and/or mutations associated with complement evasion. Using this data, we will employ machine learning and statistical analysis to predict the immune evasiveness of an isolate directly from the bacterial genome sequence, an important step towards understanding pathogenicity and improving disease management.

APPLICATIONS:

Applicants must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree (or equivalent) in a relevant discipline. Experience working in a microbiology/ immunobiology or molecular biology is preferred but not essential. We are seeking candidates with a strong interest in host-pathogen interactions with motivation to explore and better understand the molecular basis of pathogen immune evasion.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form: https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl-2

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding form the DTP will be required to submit an application to study at Bath.

More information on the application process may be found here:
https://www.gw4biomed.ac.uk/doctoral-students/

APPLICATIONS CLOSE AT 17:00 ON 23 NOVEMBER 2020.

Funding Notes

UK students will be considered for a full 3.5-year studentship consisting of UK tuition fees, a Research and Training Support Grant of £2000-£5000 per annum and a stipend (£15,285 per annum for 2020/21, updated each year).

International applicants (including EU applicants) are also eligible to apply but will be required to pay the difference between the Home UKRI tuition fee View Website and the applicable University of Bath Overseas tuition fee rate View Website. Confirmation of ability to fund the tuition fee difference will be required.

References

M. Laabei et al., “Antibacterial fusion proteins enhance Moraxella catarrhalis killing,” Front Immunol. 10.3389/fimmu.2020.02122. Sep 2020.

D. Ermert et al., “The hijackers guide to escaping complement: Lessons learned from pathogens,” Mol Immunol. Oct;114:49-61. doi: 10.1016/j.molimm.2019.07.018. Epub 2019 Jul 20.

M. Recker et al., "Clonal differences in Staphylococcus aureus bacteraemia-associated mortality," Nat Microbiol, vol. 2, no. 10, pp. 1381-1388, Oct 2017.

M. Laabei et al., "Predicting the virulence of MRSA from its genome sequence," Genome Res, vol. 24, no. 5, pp. 839-49, May 2014.

M. Laabei et al., "Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus," PLoS Biol, vol. 13, no. 9, p. e1002229, 2015.

M. Laabei and R. Massey, "Using functional genomics to decipher the complexity of microbial pathogenicity," Curr Genet, vol. 62, no. 3, pp. 523-5, Aug 2016.

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