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New treatments for antimicrobial resistant TB via modulation of innate immunity

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  • Full or part time
    Dr P Elks
    Prof S Renshaw
  • Application Deadline
    No more applications being accepted

Project Description

Neutrophils are the most abundant white blood cell type and are able to directly kill invading pathogens using a powerful artillery at their disposal. However, they are classically seen as being a blunt tool against infection that can cause surrounding tissue damage and chronic inflammatory diseases.

Our disease of interest is tuberculosis, a bacterial infection on the rise due to the increasing prevalence of multi-drug resistance. We use the zebrafish embryo infected with Mycobacterium marinum (Mm, fish TB) in combination with a tailfin inflammation model to understand how infection and inflammation are managed in an individual organism. Our lab has a focus on genetic hypoxia signalling (via the transcription factor Hif-alpha). Hif-1alpha stabilisation protects against infection but also leads to prolonged neutrophil inflammation, negatively affecting inflammation and tissue remodelling (Elks et al., 2013. http://goo.gl/CxdYld). Two Hif-alpha variants, Hif-1alpha and Hif-2alpha, have opposing effects on neutrophil antimicrobial activity but have a similar effects on neutrophil behaviour during inflammation.

In this project we aim to understand whether neutrophils can be molecularly tuned, by modulating Hif-1alpha and Hif-2alpha appropriately, to better kill infection while not causing excess inflammation.

Specifically, we aim to address:
1. How Hif-alpha signalling alters neutrophil migratory behaviours and decision making to sites of a wound or infection.
2. Whether Hif-alpha variants can be modulated to improve infection outcomes without negative inflammatory effects.

The dual infection and inflammation model is recently developed in the lab and has so far produced exciting results that require a PhD student to take it forwards. The role of the neutrophil during TB remains understudied, especially in in vivo models of infection.
Neutrophil migratory behaviour will be assessed in the in vivo zebrafish using timelapse fluorescence microscopy to observe decision making between infection and wounds after Hif-alpha variant manipulation. Links between Hif-alpha signalling and neutrophil phenomena including neutrophil swarming and NET (neutrophil extracellular trap) formation will be explored to uncover novel molecular mechanisms.
Hif-1alpha and Hif-2alpha will be modulated using dominant constructs and novel neutrophil specific CRISPRi (CRISPR mediated interference) to assess the outcomes of infection and inflammation in the dual model. The downstream targets of Hif-1alpha and Hif-2alpha will be assessed by FACs sorting of neutrophils from Hif-alpha modulated embryos and performing RNAseq analysis.

This work will take place in a young and vibrant research group (http://elkslab.weebly.com/) and the candidate will be trained in molecular biology and microscopy techniques.

Funding Notes

The UPGRC Scholarships for Medicine, Dentistry & Health are 3.5 years in duration and cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.

This project is also being advertised for the China Scholarship Council Award, further details can be found here: https://www.sheffield.ac.uk/postgraduate/phd/scholarships/csc

Eligibility:
In vivo research experience desirable

References

1. Ellett F, Elks PM, Robertson AL, Ogryzko NV, Renshaw SA (2015) Defining the phenotype of neutrophils following reverse migration in zebrafish. J Leukoc Biol. 2015 Jun 12. pii: jlb.3MA0315-105R.

2. Elks PM, Van Der Vaart M, Van Hensbergen V, Schutz E, Redd MJ, Murayama E, Spaink HP & Meijer AH (2014) Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model. PLoS ONE, 9(6).

3. Elks PM, Brizee S, van der Vaart M, Walmsley SR, van Eeden FJ, Renshaw SA & Meijer AH (2013) Hypoxia inducible factor signaling modulates susceptibility to mycobacterial infection via a nitric oxide dependent mechanism.. PLoS Pathog, 9(12), e1003789. View this article in White Rose Research Online

4. Elks PM, Van Eeden FJ, Dixon G, Wang X, Reyes-Aldasoro CC, Ingham PW, Whyte MKB, Walmsley SR & Renshaw SA (2011) Activation of hypoxia-inducible factor-1α (hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Blood, 118(3), 712-722.

5. Bagnall J, Leedale J, Taylor SE, Spiller DG, White MR, Sharkey KJ, Bearon RN, Sée V (2014) Tight control of hypoxia-inducible factor- transient dynamics is essential for cell survival in hypoxia. J Biol Chem. 2014 Feb 28;289(9):5549-64. doi: 10.1074/jbc.M113.500405. Epub 2014 Jan 6.



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