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GW4 BioMed2 MRC DTP PhD project - Escaping host immunity: Characterising immune evasion mechanisms employed by the bacterial pathogen Staphylococcus aureus


   Department of Life Sciences

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  Dr Maisem Laabei  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is one of a number that are in competition for funding from the GW4 BioMed2 MRC Doctoral Training Partnership which is offering up to 20 studentships for entry in October 2023.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found on the DTP’s website.

SUPERVISORY TEAM:

  • Dr Maisem Laabei (lead), University of Bath, Department of Life Sciences
  • Prof Ruth Massey, University of Bristol, School of Cellular and Molecular Medicine
  • Dr Mario Recker, University of Exeter, Centre for Mathematics and the Environment
  • Prof Jean van den Elsen, University of Bath, Department of Life Sciences

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 develop effective 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-omics 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, previously collected clinical data and machine learning, the project aims to identify 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 host 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, the student 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, express and purify recombinant staphylococcal surface 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 hypothesise 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 the student will use promoter-reporter plasmids and cutting-edge transcriptomic analysis, employing dual GFP/Lux reporter vectors and high-resolution RNA sequencing to determine differential gene expression under lab and in vivo like conditions. The student will steer this objective by investigating the effects of different growth media reflecting infectious conditions on complement evasion expression. These environmental specific global gene expression profiles will be used to reveal the regulatory framework responsible for complement resistance in S aureus.

Lastly, the student 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, the student will optimise machine learning methodology to predict the immune evasiveness of an isolate directly from the bacterial genome sequence, an important step towards understanding pathogenicity and improving disease management.  

REQUIREMENTS: 

Applicants must have obtained, or be expected to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Academic qualifications are considered alongside significant relevant non-academic experience.

Non-UK applicants will also be required to have met the English language entry requirements of the University of Bath.

ENQUIRIES AND APPLICATIONS: 

Informal enquiries are welcomed and should be directed to Dr Maisem Laabei on email address [Email Address Removed].

Formal applications must be submitted direct to the GW4 BioMed2 DTP using their online application form.

A list of all available projects and guidance on how to apply may be found on the DTP’s website. You may apply for up to 2 projects.

APPLICATIONS CLOSE AT 17:00 (GMT) ON 2 NOVEMBER 2022.

IMPORTANT: 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 from the DTP will be required to submit an application for an offer of study from Bath.


Funding Notes

Candidates may be considered for a 4-year GW4 BioMed2 MRC DTP studentship covering tuition fees, a stipend (£17,668 p/a in 2022/23) and a Research & Training Support grant of between £2,000 and £5,000 p/a dependent on project requirements. Studentships are open to both Home and International students; however, International applicants should note that funding does NOT cover the cost of a student visa, healthcare surcharge and other costs of moving to the UK. In line with guidance from UK Research and Innovation (UKRI), the number of awards available to International candidates will be limited to 30% of the total.

References

• M. Laabei et al., “Significant variability exists in the cytotoxicity of global methicillin-resistant Staphylococcus aureus lineages” Microbiology. doi: 10.1099/mic.0.001119. Dec 2021
• 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., "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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