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4-year PhD Studentship: Sticky but not sweet: deciphering how Streptococcus bacteria drive clot formation and heart disease

   Faculty of Health Sciences

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  Dr A Nobbs, Dr B Amulic, Prof Paul Race  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Heart disease is the leading cause of mortality in the developed world. Viridans group Streptococcus bacteria (VGS) are a major cause of infective endocarditis (IE), a severe form of heart disease characterised by clot formation on heart valves[1,2]. IE has a high mortality rate, is lethal if untreated, and treatment often fails due to inadequate antibiotic penetration into infective clots or bacterial antibiotic resistance. Moreover, incidence of disease in the US and UK is increasing[3-5]. This indicates an unmet clinical need for development of non-antibiotic based strategies for the management of IE.

Critical to IE, VGS can survive within blood and activate platelets on heart valves. Our work with VGS Streptococcus gordonii has shown that surface protein PadA triggers platelet activation via receptor GPIIbIIIa. We have also found that PadA modulates neutrophil extracellular trap (NET) formation, promotes bacterial survival in blood, and contributes to virulence in a rabbit IE model[6-8]. These data provide strong evidence that PadA is critical to IE pathogenesis. However, the mechanistic detail of how PadA mediates these effects is unknown. Furthermore, PadA homologues are found across several VGS species but it is not known if these confer similar functional capabilities. This project addresses these critical questions.

Aims and Objectives

There is strong evidence that PadA is critical to the capacity of VGS to cause IE. This project therefore aims to identify the precise molecular mechanisms by which PadA promotes bacterial survival within the bloodstream and drives the unwanted clot formation associated with IE. Such mechanistic understanding is a critical first step to the development of novel therapies for IE. The specific objectives are:

  1. Identify the mechanisms by which PadA modulates platelet and neutrophil behaviour
  2. Identify the mechanisms by which PadA promotes survival within blood
  3. Perform structural characterisation of PadA
  4. Assess PadA homologues from clinical isolates


A panel of bacterial mutants, recombinant protein (rPadA) and primary human cells will be used to reveal the downstream signalling events mediated by PadA that culminate in platelet spreading and aggregation and to investigate the capacity for PadA to evade neutrophil- or complement-mediated killing. Studies will explore phagocytic killing, cytokine release, serum bactericidal activity, binding of complement inhibitors/serum proteins and deposition of complement factors. Neutrophil activation and NET formation will be monitored to assess if platelets/VGS trigger NETs as a scaffold to enhance clot formation.

Structural resolution of PadA is critical to design targeted therapeutic strategies. Crystallisation and co-crystallisation with known ligands (e.g. GPIIbIIIa) will be performed with domains of rPadA. Stability and flexibility will be assessed with combined biophysical and hydrodynamic approaches to understand how PadA functions under the shear forces of the cardiovascular system.

Severn Pathology has a well-curated collection of VGS isolated from IE patients. This will be exploited to extend PadA studies beyond S. gordonii, enhancing the clinical relevance of this work. IE strains will be screened for PadA (gene/protein) and compared with VGS isolates from non-IE patients. Functional capabilities of PadA homologues with regards to platelet/neutrophil interactions and blood survival will be determined.


Heart disease, bacterial pathogenesis, immune evasion, structural biology, molecular microbiology

How to apply for this project

This project will be based in Bristol Dental School in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply

Funding Notes

This project is open for University of Bristol PGR scholarship applications (closing date 25th February 2022)
The University of Bristol PGR scholarship pays tuition fees and a maintenance stipend (at the minimum UKRI rate) for the duration of a PhD (typically three years but can be up to four years).
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