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MRC DiMeN Doctoral Training Partnership: Interbacterial competition during Mycobacterium abscessus colonisation of the lung in people with cystic fibrosis


Project Description

Cystic fibrosis (CF) is the most common life-limiting genetic disorder in the UK. Respiratory infection is responsible for the majority of morbidity and mortality. Mycobacterium abscessus is multi-drug resistant, associated with poor clinical outcomes and a barrier to lung transplantation in people with CF. Rates of infection in people with CF are rising annually and treatment is rated a top CF research priority. Currently little is known about the strategies M. abscessus uses to compete with the resident microbiota. Recent work has indicated that the Type VII protein secretion system (T7SS) secretes toxins that inhibit the growth of competitor bacteria, potentially playing an important role in shaping bacterial communities (1). Genomic analysis reveals that M. abscessus encodes two Type VII protein secretion systems and that all strains encode at least one T7-dependent antibacterial toxin. This project will be co-supervised by Professor Tracy Palmer (https://www.ncl.ac.uk/camb/staff/profile/tracypalmer.html#background) and Dr Malcolm Brodlie (https://www.ncl.ac.uk/icm/people/profile/malcolmbrodlie.html#background and crg.org.uk) and the aim is to characterise T7-secreted antibacterial toxins of M. abscessus and assess their role in colonisation.

Potential toxins identified by genomic analysis will be cloned into tightly-regulatable vectors to assess for toxic activity in E. coli and M. abscessus. Neighbouring genes will be cloned to assess whether they act as antitoxins and whether they with toxins in 2-hybrid assays. Genomic deletions will be constructed in the M. abscessus T7SSs and the effect of these mutations on the ability to secrete epitope-tagged versions of the toxins will be assessed. M. abscessus strains lacking the toxins and antitoxins will be constructed and used in competition experiments with other members of the lung microbiota. The zebrafish larvae infection model and the air-liquid interface epithelial model will be used to assess whether toxins contribute to virulence and to biofilm formation. All techniques are currently in use in the supervisors’ laboratories (2,3).

Follow us on twitter @proftracypalmer and @malc_brod

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 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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

References

1. Cao et al. 2016) The Type VII secretion system of Staphylococcus aureus secretes a nuclease toxin that targets competitor bacteria. Nature Microbiology. 10, 16183.

2. Grassmé et al. (2017) β1-Integrin accumulates in cystic fibrosis luminal airway epithelial membranes and decreases sphingosine, promoting bacterial infections Cell host & microbe 21 (6), 707-718. e8

3. Ulhuq et al. (2019) A membrane-depolarising toxin substrate of the Staphylococcus aureus Type VII protein secretion system targets eukaryotes and bacteria. BioRxiv http://biorxiv.org/cgi/content/short/443630v1

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