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Molecular characterisation of novel virulence genes and vaccine candidates in pathogenic Corynebacterium diphtheria (Ref: SF20/APP/SANGAL)

  • Full or part time
    Dr V Sangal
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Corynebacterium diphtheriae is a prominent human pathogen that causes diphtheria, a toxin mediated disease of upper respiratory tract, resulting in significant mortality and morbidity in humans. Despite the use of an effective toxoid vaccine, a number of outbreaks have been reported globally (Sangal & Hoskisson, 2016). In addition, nontoxigenic C. diphtheriae strains are increasingly isolated from severe invasive infections such as endocarditis, septic arthritis and osteomyelitis (Edwards et al., 2011, Ramdhan et al., 2019). We have analysed the genome sequences of a number of toxigenic and non-toxigenic C. diphtheriae strains from different countries (Sangal et al., 2015, Grosse-Kock et al., 2017). These studies identified a variation in the evolutionary dynamics of the toxigenic and non-toxigenic strains (Grosse-Kock et al., 2017) but also highlighted the variation in the gene content that is responsible for the differences in the propensities of C. diphtheriae infections (Sangal et al., 2015, Ott et al., 2017).

Our genomic analyses also identified a number of genes encoding membrane-associated, cell envelope and secreted proteins potentially associated with the virulence and exploitable characteristics (unpublished data). This study will focus on characterisation of membrane-associated genes which are likely to effect the optimal functioning of the cell envelope of C. diphtheriae. The candidate genes will be characterised using approaches of molecular genetics (e.g., generating gene knock-out strains with the loss of gene functions) and characterisation of these strains using approaches including electron microscopy, genomics, transcriptomics and proteomics to study morphological and biochemical dysfunctions. The impact of the loss of gene functions on strain virulence will be characterised by in vivo survival assays in the macrophages and invertebrate infection models. The restoration of gene functions in mutant strains will be studied using complementation experiments. The potential of these genes to use as vaccine candidates with be explored.

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.

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: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed and the reasons you consider yourself suited to the project. Applications that do not include the advert reference (e.g. SF20/…) will not be considered.

Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March

Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.

Please direct enquiries to Dr Vartul Sangal ()

Funding Notes

Please note, this is a self-funded project and does not include tuition fees or stipend; the studentship is available to Students Worldwide. Fee bands are available at View Website . A relevant fee band will be discussed at interview based on project running costs.

References

1. Edwards B, Hunt AC & Hoskisson PA (2011) Recent cases of non-toxigenic Corynebacterium diphtheriae in Scotland: justification for continued surveillance. J Med Microbiol 60: 561-562.

2. Grosse-Kock S, Kolodkina V, Schwalbe EC, et al. (2017) Genomic analysis of endemic clones of toxigenic and non-toxigenic Corynebacterium diphtheriae in Belarus during and after the major epidemic in 1990s. BMC Genomics 18: 873.

3. Ott L, Hacker E, Kunert T, et al. (2017) Analysis of Corynebacterium diphtheriae macrophage interaction: Dispensability of corynomycolic acids for inhibition of phagolysosome maturation and identification of a new gene involved in synthesis of the corynomycolic acid layer. PLoS One 12: e0180105.

4. Ramdhan ND, Blom J, Sutcliffe IC, Pereira-Ribeiro PMA, Santos CS, Mattos-Guaraldi AL, Burkovski A & Sangal V (2019) Genomic analysis of a novel nontoxigenic Corynebacterium diphtheriae strain isolated from a cancer patient. New Microbes New Infect 30: 100544.
5. Sangal V & Hoskisson PA (2016) Evolution, epidemiology and diversity of Corynebacterium diphtheriae: New perspectives on an old foe. Infect Genet Evol 43: 364-370.

6. Sangal V, Blom J, Sutcliffe IC, von Hunolstein C, Burkovski A & Hoskisson PA (2015) Adherence and invasive properties of Corynebacterium diphtheriae strains correlates with the predicted membrane-associated and secreted proteome. BMC Genomics 16: 765.

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