New disease prevention strategies targeting BK polyomavirus infection informed by whole-genome CRISPR-knockout screening and/or apical extrusion.


   York Biomedical Research Institute

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  Dr Simon Baker, Dr W Brackenbury, Dr Andrew Mason  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

BK virus is a ubiquitous childhood infection that persists in the kidney throughout adult life. BK virus reactivation under immunosuppression is responsible for one third of kidney transplant failures and a three-fold greater risk of bladder cancer in kidney transplant recipients. We recently published data supporting the hypothesis that BK virus infections can cause the mutations seen in bladder cancers (Oncogene 2022;41(15):2139-2151). As the next step, you will seek interventions to reduce the risks of the wide range of urinary tract pathologies driven by BK virus infections.

We have developed an experimental cell and tissue culture platform to study the consequences of BK virus-infection of one normal human urinary tract epithelium, the urothelium. Our models recapitulate both the luminal cell surface that represents the site of infection and the chronic duration of clinical BK virus-infections caused by the initial viral-mediated drive of G0-arrested urothelial cells into the cell cycle.

A critical part of the urinary tract response to infection is epithelial extrusion of infected “decoy” cells by the renal epithelium and urothelium, but there have been no models of this phenomenon until now. Because apical extrusion does not rely on immune cells, it is possible that this innate mechanism of clearing infection from the afflicted epithelial tissues could be enhanced during immunosuppression without risking rejection.

In this PhD you will seek new approaches to BK virus-specific antiviral therapy driven by greater knowledge of disease-relevant urinary tract biology. We propose two approaches. The first relies on CRISPR-knockout technology already established in the lab of our collaborator, Professor Colin Crump (University of Cambridge) using renal cells. CRISPR-knockouts may not succeed in the urothelial cell system and we have de-risked the studentship to ensure success by having a second objective with robust preliminary results.

Objectives

1. Preventing infection of normal human urothelial cells using a genome-wide pooled CRISPR-knockout screen. BK virus infections are lytic and therefore lethal to cells when unimpeded. Cells surviving BK virus-infections will harbour knockouts for genes necessary for the viral life cycle. Your data will synergise with our collaborator’s CRISPR-knockout in renal cells to deliver robust pan-urinary tract targets to fight infection.

2. Establish the potential of enhancing the apical extrusion of infected epithelial cells as a novel therapeutic approach in the immunosuppressed. We have established a novel model of human ureteric organotypic infection where the local reaction to BKPyV leads to encapsulation of infected cells and ultimately their apical extrusion into the “urine”. Stimulating this pathway, so the tissue becomes more sensitive to the changes in infected cells, could lead to early clearance of the virus, preventing disease.

Based on the data developed during this studentship we propose to test existing (and/or develop new) pharmacological modulators of the BK virus-infection biology we observe for disease prevention.

The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation, religion/belief, marital status, pregnancy and maternity, or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

Supervisor’s Twitter/X Profile: @Dr_Simon_Baker

Supervisor’s Website: https://www.york.ac.uk/biology/research/infection-immunity/simon-baker/

Link to the Oncogene paper cited in the text: https://www.nature.com/articles/s41388-022-02235-8


Biological Sciences (4) Medicine (26)

Funding Notes

This studentship is fully funded by Kidney Research UK and covers: (i) a tax-free stipend at the standard UKRI rate for doctoral students, (ii) research costs, and (iii) tuition fees at the UK rate.

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