MRC DiMeN Doctoral Training Partnership: Unveiling novel interactions between the human complement system and pathogenic Neisseria

Description

Primary Supervisor:

Dr. Hayley Lavender (https://www.liverpool.ac.uk/people/hayley-lavender)

Secondary Supervisors:

Prof. Kevin Marchbank (https://www.ncl.ac.uk/medical-sciences/people/profile/kevinmarchbank.html)

Prof. Aras Kadioglu (https://www.liverpool.ac.uk/bacterial-pathogenesis)

Project Overview: Neisseria meningitidis, the causative agent of life-threatening meningitis and septicaemia, and Neisseria gonorrhoeae, a designated 'superbug' responsible for the sexually transmitted infection, gonorrhoea, represent critical public health threats. Despite advances in vaccination, meningococcal infections are on the rise, prompting health advisories from the CDC. The global surge in gonococcal infections, and increased antimicrobial resistance to last-line treatments, has led to both the WHO and CDC to classify N. gonorrhoeae as a high-priority pathogen. Understanding the immune evasion strategies of Neisseria is paramount for the design of novel drug and vaccine interventions

Research Aim: This PhD project seeks to dissect the molecular mechanisms that Neisseria spp. use to manipulate the host immune system, focusing specifically on the interactions of the Factor H-Related Proteins (FHRs) a component of the human complement system—an essential first line of defence against infections. This study will delve into how FHRs modulate complement activation and how their interactions with Neisseria contribute to disease progression.

Scientific Significance: Our recent discoveries have shown that FHRs act as antagonists of Factor H (FH), a key negative regulator of complement activity. Recruitment of FHRs allows for "fine-tuning" of the immune response on the bacterial surface. FHRs play a pivotal role in infection outcomes, yet their full impact on Neisseria pathogenesis remains underexplored. Uncovering the molecular interactions between FHRs and Neisseria could lead to novel therapeutic targets that disrupt this immune manipulation, offering potential breakthroughs in combating both meningococcal and gonococcal infections.

Key Objectives:

• Identify novel interactions between Neisseria and FHRs, providing fresh insights into how these pathogens subvert complement regulation.
• Determine how FHR recruitment influences complement deposition on the bacterial surface,
• Define the role of FHRs in shaping infection outcomes, linking molecular mechanisms to host-pathogen interactions.

Research Approach: The project will utilise a multidisciplinary approach, integrating microbiology, cell biology, and biochemistry, alongside both in vitro and in vivo infection models. This will provide a comprehensive understanding of Neisseria's immune evasion strategies, from molecular binding events to the broader implications on infection and disease progression.

Training and Skill Development: As part of this PhD, you will receive extensive training in bacterial pathogenesis, immune evasion, and complement biology, gaining hands-on experience with both laboratory-based techniques and in vivo infection models. You will become adept at investigating host-pathogen interactions, building a versatile skill set that is directly applicable to fields like infectious disease research, immunology, and molecular biology.

Impact: This research has the potential to uncover novel immune evasion mechanisms employed by Neisseria, informing the design of next-generation vaccines or therapeutic interventions. By deepening our understanding of how pathogens exploit host immune regulators, this project could open the door to new strategies for tackling the rising threat of antibiotic-resistant infections.

In sum, this project is a unique opportunity to contribute to high-impact research at the intersection of microbiology, immunology, and infectious disease, to combat bacterial infections. 

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/