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Functional and immune characterisation of a novel adhesin of Bordetella pertussis the causative agent of Whooping Cough (REF: RDF22/HLS/APP/MACARTHUR)


   Faculty of Health and Life Sciences

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  Dr Iain MacArthur, Dr LG Dover, Dr Monica Cartelle Gestal  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The bacterium Bordetella pertussis colonises the trachea of susceptible humans – mainly unvaccinated children – causing pertussis, an infection also commonly known as Whooping cough, is characterised by low-grade fever, a paroxysmal cough leading to the deep intake of breaths resulting in the “whooping” sound, cyanosis, and post-tussive emesis. Although, the incidence of pertussis reduced drastically following the introduction of whole-cell vaccines in the late 1960s, there has been a notable and unexplained increase in cases since late 2011.

This recent resurgence of Whooping cough has revealed a surprising lack of understanding of pertussis – specifically the mechanisms of pathogenesis and the nature of the protective immunity induced by different vaccines. It’s clear that we need a better understanding in the increase in cases of pertussis, and devise methods to halt it, such as the development of novel vaccines that can be targeted to induce more effective and longer-lasting immunity that can reduce initial colonisation of the host. We have identified a putative cell surface component, a novel adhesin comprised of two subunits, one with homology to pertussis toxin subunit ptxB/C and the other with homology to subtilysin. Both are under the regulation of the BvgAS two-component system that also regulates the expression of key virulence determinants. Initial analysis of these mutants has shown that they have a significant role in the binding to epithelial cells, with a 2-log reduction in binding to epithelial cells compared to wild-type. The characterisation of putative novel adhesins is clearly of importance to this.

We will systematically mutate genes encoding putative novel adhesins of B. pertussis, in combination with a proteomic characterisation of their interaction with host cells. We will take two approaches to assess virulence. Firstly, we will use a recognised mouse model, in collaboration with Dr. Monica Cartelle Gestal, (Louisiana State University), to determine the ability of the mutants to colonise three distinct respiratory tract regions (nasal cavity, trachea and the lung) and their transmission from colonised to naïve mice. Secondly, we will analyse the mutants in vitro using adherence to epithelial cells, with immunofluorescence to identify the location of the protein (either on the cell surface or within the cell) and to determine cytotoxicity. Specific adhesin ligand interaction will be determined using pull-down assays to identify host cell ligands. Immunogenicity of each of the bacterial proteins will be determined and cognate antibodies used in neutralization assays to identify those that limit bacterial adhesion to epithelial cells and/or cytotoxicity. Finally, we will use a vaccination challenge approach in mice to prioritise candidate proteins for inclusion in future vaccine formulations.

Supervisory Team:

Dr. Iain MacArthur & Dr Lynn Dover, Northumbria University, Department of Applied Sciences

Dr. Monica Cartelle Gestal, LSU Health Science Shreveport, USA

Eligibility and How to Apply:

Please note eligibility requirement:

·      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.

·      Appropriate IELTS score, if required.

·      Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere or if they have previously been awarded a PhD.

For further details of how to apply, entry requirements and the application form, see

https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/ 

 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. RDF22/…) will not be considered.

Deadline for applications: 18 February 2022

Start Date: 1 October 2022

Northumbria University takes pride in, and values, the quality and diversity of our staff and students. We welcome applications from all members of the community.

Informal enquiries to Dr Iain MacArthur ([Email Address Removed]).


Funding Notes

Each studentship supports a full stipend, paid for three years at RCUK rates (for 2021/22 full-time study this is £15,609 per year) and full tuition fees. UK and international (including EU) candidates may apply.
Studentships are available for applicants who wish to study on a part-time basis over 5 years (0.6 FTE, stipend £9,365 per year and full tuition fees) in combination with work or personal responsibilities.
Please also read the full funding notes (https://www.northumbria.ac.uk/research/postgraduate-research-degrees/studentships/rdf) which include advice for international and part-time applicants.

References

Belcher, T., MacArthur, I., King, J.D., Langridge, G.C., Mayho, M., Parkhill, J. and Preston, A., 2020. Fundamental differences in physiology of Bordetella pertussis dependent on the two-component system Bvg revealed by gene essentiality studies. Microbial genomics, 6(12), p.e000496.
Ring, N., Abrahams, J.S., Bagby, S., Preston, A. and MacArthur, I., 2019. How Genomics Is Changing What We Know About the Evolution and Genome of Bordetella pertussis. Pertussis Infection and Vaccines: Advances in Microbiology, Infectious Diseases and Public Health Volume 12, pp.1-17.
MacArthur, I. and A. Preston. 2018. Congenerics: What can be learned about pertussis from pertussis-like disease caused by other Bordetella? In: Pertussis: epidemiology, immunology, & evolution. Edited by Pejman Rohani and Samuel V. Scarpino: Oxford University Press.
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