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A proteomic map of host cell rewiring by pathogens

School of Biological Sciences | PHD

Applications are now CLOSED
Funding
Funded
Reference Number
SBIO-2020-1082
Application Deadline
31 March 2020
Start Date
1 October 2020

Overview

We aim to develop advanced methods in mass spectrometry-based proteomics and apply them to the question of how host cellular defences are manipulated by bacterial pathogens.

Bacterial pathogens residing within host cells must subvert cellular defences in order to avoid destruction and progress infection. The mechanisms by which bacteria can 'rewire' host cell functions are poorly understood. The delineation of mechanistic details of how host defence systems are manipulated by pathogens is a key goal in contemporary infection biology research and success in this area may lead to the identification of pharmacological intervention targets in the host cell1. This host-directed strategy is attractive from the perspective of antimicrobial resistance (AMR) as it sidesteps the possibility of pathogens evolving resistance by targeting host components of bacterial rewiring.

The principal targets for pathogenic host cell manipulation are the primary functional units of the cell, namely proteins. The functional state of proteins depends on their cellular abundance, post translation modification (PTM) status, and assembly into protein complexes. To assess the state of the proteome we require quantitative measurement technologies. We have recently jointly developed diaPASEF2,3, a mass spectrometry method for sensitive protein quantification from minute quantities of protein (10-200ng) that can be applied to at high throughput (up to 50 samples per day). In this project, we will extend/optimize diaPASEF to assess the state of the proteome during the course of cellular infection with bacterial pathogens. Specifically, our aims are:

(1)Extend the diaPASEF method by:

(i)Optimize the diaPASEF parameter space to maximize ion utilization and selectivity enabling deep proteome coverage

(ii)Adapt diaPASEF for samples enriched for PTMs with relevance in host cell infection biology (phosphorylation, ubiquitination, ISGylation, sumoylation, neddylation)

(iii)Extend diaPASEF for use with our previously developed methods for targeted and global assessment of protein complex assembly state4,5

(2)Apply the methods developed to measure protein abundance, PTM state, and protein complex assembly state, in a host-centric approach to delineating bacterial rewiring in 2 clinically relevant pathogens:

(i)Klebsiella pneumonia is a global concern due to the increasing isolation of multidrug resistant strains. Klebsiella targets PTMs (SUMOylation, Neddylation and ISGlyation) to promote infection, however there is a lack of understanding of which are the critical PTMs modified proteins counteracting the infection. (collaboration with Bengoechea lab)

(ii)Legionella pneumophila, is an emerging respiratory pathogen and the cause of Legionnaires’ disease. L. pneumophila injects more than 300 effector proteins into macrophages and epithelial cells. These actively change the host proteome and signalling, through modulation of translation, cellular stress responses and the ubiquitin system, ultimately establishing an intracellular niche for replication. The function of the majority of effectors and a global view of the changes occurring remain elusive. (collaboration with Schroeder lab).

These pathogens utilize diverse virulence mechanisms and, as such, will demonstrate the broad applicability of our method. The results will provide a broad, dynamic, and integrated map of the host systems targeted by each pathogen. We will assess the functional consequences of removing selected key host cell proteins (by knockdown/out, chemical inhibition) using standard infection assays. Overall, the outcome will be a broadly applicable approach to determine mechanisms of host-cell rewiring demonstrated in 2 clinically relevant bacterial pathogens.

The project will be supervised by Dr Ben Collins (Queen’s University School of Biological Sciences/Institute for Global Food Security), Professor Jose Bengoechea and Dr Gunnar Neels Schroeder (Queen’s University School of Medicine, Dentistry and Biomedical Sciences), and Dr Stephanie Kaspar Schoenfeld (Bruker Daltonics).

Skills required by applicants:

The student should have a background or interest in learning skills in the following areas:
- Mass spectrometry based proteomics
- Cellular microbiology and host-pathogen interactions
- Bioinformatics and statistics

However, the student will be trained in advanced mass spectrometry methodology and computational methods (Collins lab and Bruker Daltonics) and cellular microbiology (Bengoechea and Schroeder labs). The student will be expected to make a number of research visits to Bruker Daltonics (Bremen, Germany) and budget for research visits and additional training courses has been reserved.

1Zumla, A. et al. Lancet Infect. Dis. 16, e47–e63 (2016).

2Meier, F. et al. bioRxiv 656207 (2019).

3diaPASEF: data independent acquisition – parallel accumulation serial fragmentation

4Heusel, M. et al. Mol. Syst. Biol. 15, e8438 (2019).

5 Collins, BC et al. Nature Methods 10, 12 (2013): 1246–53.

Funding Information

The studentship will be funded by the Department for the Economy (DfE) and Bruker Daltonics (industrial partner).

Only UK/EU students are eligible to apply. Please read the full information on eligibility criteria: https://www.economy-ni.gov.uk/publications/student-finance-postgraduate-studentships-terms-and-conditions

Not all applicants may be eligible to receive a full studentship - please note the Residency and Citizenship requirements in the document linked to above.

Project Summary
Supervisor
Dr Ben Collins
Mode of Study

Full-time: 3 years


Funding Body
DfE/Bruker Daltonics
Apply now Register your interest

Biological Sciences overview

COVID-19 UPDATE: The University is open and ready to take new postgraduate research students, though we are having to take precautions in the laboratory environments, involving social distancing and the mandatory use of Personal Protective Equipment (mainly gloves and masks) and strong hygiene measures to ensure safety. Please refer to Our Campus Commitment for further information: http://www.qub.ac.uk/our-campus-commitment/

The School of Biological Sciences provides PhD and MPhil (research degree) programmes in subjects ranging from basic biochemistry, molecular genetics and cancer research, to agricultural science, marine ecology and the economic evaluation of ecosystem services and food retailing. If you have a topic or research question in mind, please use the Find a Supervisor link (see Apply tab) to identify the most appropriate member of staff to support your idea. If not, don't worry, we regularly advertise funded projects and there is no harm in browsing our academic staff profiles for inspiration and then contacting whoever seems best: we are very open to applications from suitably qualified people interested in scientific research. In every case, a PhD or MPhil course provides the means of being part of a cutting edge scientific research team and contributing to genuine new discoveries or the development of new methods for practical use. If you cannot study full time, we offer pro-rata part time research degree programmes as well.

To help orientation, the School is organised into three research theme clusters:

- Ecosystem Biology and Sustainability
- Microbes and Pathogen Biology
- Food Safety and Nutrition

Ecosystem Biology and Sustainability:

In this cluster, you could research biodiversity and ecosystem services for environments ranging from tropical forests to deep oceans, using field techniques and skills such as wildlife tracking, taxonomy, geostatistics, molecular and genetic ecology, foodweb-analysis, microcosm and mesocosm experiments and mathematical/computational methods. Alternatively, you could study the behaviour and temperament of wild, agricultural or domestic animals and their implications for welfare and ability to respond to environmental change. Potential research projects include phylogenetic analysis of rare and newly discovered species, examination of ecological interactions in tropical systems, agricultural soils, or marine communities, using state-of-the-art genetic analysis, surveys using drones or satellite tagging, or experiments in tanks and field plots, including careful and ethical examinations of animal behaviour. Projects range from theoretical analysis of stability in ecosystems, through discovery of new species and mechanisms of interaction, or responses to climate change, to the assessment of EU agri-environment schemes, development of new methods for commercial fisheries management and economic evaluations of conservation measures. Projects very often have an international dimension and include collaboration with other researchers worldwide.

Microbes and Pathogen Biology:

This cluster covers a diverse array of research interests united by an emphasis on molecular approaches applied to both fundamental and applied questions over the range from molecular to ecological systems. These interests include biochemistry, food safety, microbiology and parasite control with applications in human and animal health, nutrition, plant and soil sciences, and agricultural development. We have a long-standing reputation in parasite biology and in applied microbiology (for example in clearing land of contamination) as well as strong contributions to fundamental methods in understanding cancer, developing veterinary vaccines and molecular detectors for toxins and diseases. The common thread is our strong molecular approach using and developing cutting edge genomic, transcriptomic/proteomic methods. Research students in this cluster enjoy a range of strong international links across Europe, Asia, North and South America.

Food Safety and Nutrition:

Research opportunities offered by this cluster span the entire food chain "from farm to fork" with a strong emphasis on food safety and nutrition, public health and food security. In this cluster you would conduct research under the supervision of leading scientists based in the Institute for Global Food Security and benefit from integration with business experts, helping you gain leadership positions nationally and internationally.

Biological Sciences Highlights
Industry Links
  • The School has a wide range of strong, international links with governments, academia and industry, into which postgraduate research students are integrated.
World Class Facilities
  • Students will have the full use of modern, world-class laboratories, equipped with state-of-the-art, highly advanced analytical instruments and facilitated by world-class field work provision.
  • Students studying in the Food Safety and Nutrition programme will gain excellent practical experience of advanced technology and bioanalytical techniques for food safety analysis and monitoring, including:

    1. GC, HPLC and UPLC separation platforms;
    2. ICP, IR, qToF and QqQ mass spectrometers;
    3. Microbiological research facilities;
    4. Antibody production and biomolecule binder development;
    5. Cell culture suite and bioanalytical assay detection systems;
    6. NMR, NIR and Raman spectrometers;
    7. Proteomic and metabolomic profiling tools RT-PCR;
    8. Transcriptomic profiling;
    9. Next-generation sequencing;
    10. Multiplex biosensor platforms and LFD development.
Key Facts

  • Over 80% of science jobs are in areas of Biological Sciences.
  • Most of the critical problems facing humanity - disease, climate change and food security - require biological understanding to solve them.
Brexit Advice

Information on the implications of Brexit for prospective students.

Course content

Research Information

PhD Supervisors
Information on the research interests and activities of academics in Biological Sciences can be accessed via the School website and the Find a Supervisor facility (see Apply tab).

Career Prospects

Introduction
Queen's postgraduates reap exceptional benefits. Unique initiatives, such as Degree Plus and Researcher Plus bolster our commitment to employability, while innovative leadership and executive programmes alongside sterling integration with business experts helps our students gain key leadership positions both nationally and internationally.

Employment after the Course
Graduates have gone on to be professional research scientists, consultants, or hold technical and junior executive positions in commerce and government.

People teaching you

Dr Keith Farnsworth
Chair of School Postgraduate Research Committee
School of Biological Sciences
For a PhD you will have a principal and second supervisor who advise your independent studies and will be supported by a wider team from the academic staff - who they are, of course, depends on your project. For further details on any aspect of postgraduate research degrees within the School of Biological Sciences, contact: biosciences-pg@qub.ac.uk.

Learning Outcomes

A research degree offers students an opportunity to foster their capacity for independent research and critical thought. It also allows students to explore an area of interest and so understand and solve theoretical and practical problems within the field. Undertaking a research degree can enhance a student’s written and oral communication skills and a PhD is almost always a formal requirement for an academic post.

Course structure

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Assessment

Assessment processes for the Research Degree differ from taught degrees. Students will be expected to present drafts of their work at regular intervals to their supervisor who will provide written and oral feedback; a formal assessment process takes place annually.

This Annual Progress Review requires students to present their work in writing and orally to a panel of academics from within the School. Successful completion of this process will allow students to register for the next academic year.

The final assessment of the doctoral degree is both oral and written. Students will submit their thesis to an internal and external examining team who will review the written thesis before inviting the student to orally defend their work at a Viva Voce.

Feedback

Supervisors will offer feedback on draft work at regular intervals throughout the period of registration on the degree.

Facilities
Full-time research students will have access to a shared office space and access to a desk with personal computer and internet access.

Entrance requirements

Graduate
The minimum academic requirement for admission to a research degree programme is normally an Upper Second Class Honours degree from a UK or ROI HE provider, or an equivalent qualification acceptable to the University. Further information can be obtained by contacting the School.

International Students

For information on international qualification equivalents, please check the specific information for your country.

English Language Requirements

Evidence of an IELTS* score of 6.5, with not less than 5.5 in any component, or an equivalent qualification acceptable to the University is required (*taken within the last 2 years).

International students wishing to apply to Queen's University Belfast (and for whom English is not their first language), must be able to demonstrate their proficiency in English in order to benefit fully from their course of study or research. Non-EEA nationals must also satisfy UK Visas and Immigration (UKVI) immigration requirements for English language for visa purposes.

For more information on English Language requirements for EEA and non-EEA nationals see: www.qub.ac.uk/EnglishLanguageReqs.

If you need to improve your English language skills before you enter this degree programme, INTO Queen's University Belfast offers a range of English language courses. These intensive and flexible courses are designed to improve your English ability for admission to this degree.

As a result of the COVID-19 pandemic, we will be offering Academic English and Pre-sessional courses online only from June to September 2020.

  • Academic English: an intensive English language and study skills course for successful university study at degree level
  • Pre-sessional English: a short intensive academic English course for students starting a degree programme at Queen's University Belfast and who need to improve their English.

Tuition Fees

Northern Ireland (NI) £4,407
England, Scotland or Wales (GB) £4,407
Other (non-UK) EU £4,407
International £21,300

More information on postgraduate tuition fees.

Biological Sciences costs

Students may incur additional costs for small items of clothing and/or equipment necessary for lab or field work

Additional course costs

All Students

Depending on the programme of study, there may also be other extra costs which are not covered by tuition fees, which students will need to consider when planning their studies . Students can borrow books and access online learning resources from any Queen's library. If students wish to purchase recommended texts, rather than borrow them from the University Library, prices per text can range from £30 to £100. Students should also budget between £30 to £100 per year for photocopying, memory sticks and printing charges. Students may wish to consider purchasing an electronic device; costs will vary depending on the specification of the model chosen. There are also additional charges for graduation ceremonies, and library fines. In undertaking a research project students may incur costs associated with transport and/or materials, and there will also be additional costs for printing and binding the thesis. There may also be individually tailored research project expenses and students should consult directly with the School for further information.

How do I fund my study?
1.PhD Opportunities

Find PhD opportunities and funded studentships by subject area.

2.Doctoral Training Centres at Queen's

Queen's has eight outstanding competitive Doctoral Training Centres, with each one providing funding for a number of PhD positions and most importantly a hub for carrying out world class research in key disciplines.

3.PhD loans

The Government offers doctoral loans of up to £26,445 for PhDs and equivalent postgraduate research programmes for English- or Welsh-resident UK and EU students, £10,000 for students in Scotland and up to £5,500 for Northern Ireland students.

4.International Scholarships

Information on Postgraduate Research scholarships for international students.

Funding and Scholarships

The Funding & Scholarship Finder helps prospective and current students find funding to help cover costs towards a whole range of study related expenses.

How to Apply

Apply using our online Postgraduate Applications Portal go.qub.ac.uk/pgapply and follow the step-by-step instructions on how to apply.

Find a supervisor

If you're interested in a particular project, we suggest you contact the relevant academic before you apply, to introduce yourself and ask questions.

To find a potential supervisor aligned with your area of interest, or if you are unsure of who to contact, look through the staff profiles linked here.

You might be asked to provide a short outline of your proposal to help us identify potential supervisors.