Studies on the molecular mechanisms of bacterial virulence factors that modulate host haemostatic factors

The clotting of fibrinogen to fibrin is proposed to play a vital role in establishment of staphylococcal communities and abscess formation. Staphylocoagulase (SCG) and the recently identified von Willebrand factor binding protein (vWbp) appear to be the only coagulases in S. aureus capable of catalytically converting fibrinogen to fibrin, through the activation of prothrombin. S. aureus mutants lacking the genes for either SCG or vWbp displayed virulence defects in mouse models of infection, with both mutations exerting a lower effect independently than a double mutant strain lacking both SC and vWbp. Experimental evidence suggests the two coagulases do not fulfil identical functions during the pathogenesis of S. aureus infections in mice.

Bacterial plasminogen activators include Pla of Yersinia pestis (responsible for the bubonic plague) staphylokinase of S. aureus and streptokinase (SK) of group A, C and G streptococci. Plasmin generated by bacteria targets fibrin clots and extracellular matrix proteins of soft tissues allowing the bacteria to migrate beyond the point of infection. SK from diverse GAS have been classified into three evolutionary clusters (1, 2a and 2b) based on protein sequence variation. Cluster 2 SK variants appear to correlate with the expression of cell surface virulence determinant M-like proteins, with 2a associated with the M1 fibrinogen binding receptor and 2b with PAM, a plasminogen-binding receptor. The relationship between SK sequence variation, M-like protein association and pathogenicity is not fully understood at the molecular level.

With the increased prevalence of methicillin- and vancomycin-resistant strains of S. aureus (MRSA), and with streptococcal resistance to antibiotics increasing in response to selection pressure, multiple therapeutic approaches will eventually be needed for effective treatment of staphylococcal and streptococcal infections. Improved understanding of the mechanism of action at the molecular level and the synergistic roles between the proteins expressed by pathogenic streptococcal strains and S. aureus is essential for the development of therapies targeted towards the molecular mechanisms involved in bacterial survival and dissemination.

The project hypothesis is that the sequence differences between the coagulases of S. aureus and between the predicted GAS SK evolutionary clusters translate into differences in mechanism of action at the molecular level. Furthermore, these mechanistic differences correlate with the availability of co-factors such as bacterial cell surface receptors, and host co-factors such as fibrinogen, fibrin and vWF, which influences pathogenic processes. Finding the regulatory bottle-necks in the mechanisms of action of these virulence factors will help to identify potential targets for future therapeutic intervention.

Using recombinant protein technologies, protein biochemistry and haematology techniques you will investigate several questions including: Is there any difference between the structural and binding properties of the fibrins formed by SCG and vWbp, how does the fibrin formed compare to that of normal thrombin, and other coagulases; what are the mechanistic differences between the different SK variants of GAS, does the variation in SK protein sequence directly influence plasmin(ogen) binding and enzyme activity.

You will have:
• an academic background in the life sciences
• a demonstrated aptitude in a laboratory setting and motivation to undertake research
• a demonstrated ability to work accurately and precisely
• excellent, demonstrated oral and written communication
• a demonstrated interest in the field of study
• some knowledge and understanding of techniques described in the project

Research Environment

The successful candidate will join a collaborative effort between NIBSC the University of Leeds. You will be based primarily at NIBSC (South Mimms, Herts) with attendance at the University of Leeds for additional training. For more information about NIBSC: www.nibsc.org

Eligibility

You should hold a strong degree equivalent to at least a UK upper second class honours degree in a relevant subject area.

The Faculty minimum requirements for candidates whose first language is not English are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to Apply

To apply for this scholarship applicants should complete a Faculty Scholarship Application form using the link below http://medhealth.leeds.ac.uk/download/3551/fmh_scholarship_application_2017_18 and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School [Email Address Removed]

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [Email Address Removed] by no later than Sunday 13 August 2017

Any queries regarding the application process should be directed to [Email Address Removed]