Ejecting infection: Understanding how epithelial tissues rid themselves of viral infections by apical extrusion

Background

The epithelial tissues of our bodies use physical barriers and innate defences to fight viral infection. When infections establish, tissues can call on the immune system for assistance, but epithelia have evolved sophisticated systems to coordinate the tissue in detection, encapsulation and finally apical extrusion of infected cells.

BK polyomavirus (BKPyV) is a ubiquitous childhood infection that persists, dormant in the kidney throughout adult life and can reactivate with infected cells being extruded into the urine periodically.

BKPyV 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 evidence suggesting BKPyV may be an important risk factor for bladder cancer in the ageing general population (Oncogene 2022;41:2139–2151). In ageing or immunosuppressed patients, sub-optimal immune responses make enhancing innate epithelial clearance of viral infection an attractive approach.

Objectives

1. Identify how healthy epithelial cells detect the BKPyV-infected cells amongst them by testing hypotheses based on existing RNA-sequencing data
2. Establish how the physical processes of encapsulation and extrusion are controlled and coordinated
3. Assess approaches for enhancing innate epithelial responses for efficient clearance of BKPyV-infections

Novelty

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. We have noted cells from different donors are highly variable in how rapidly they sense and extrude infections, suggesting potential for improvement in at-risk populations.

Experimental Approach

Our research employs two models of the normal human bladder epithelium (“urothelium”):

1. in vitro tissue engineered urothelium
2. organotypic full-thickness ureter cultures

These models recreate the mitotically-quiescent and barrier-forming human tissue and show cells coordinating their behaviour to extrude their BKPyV-infected neighbours.

The lab has already generated RNA-sequencing data of BKPyV-infected urothelium at multiple timepoints which provides a number of hypothetical pathways involved in extrusion for the studentship to follow-up. State-of-the-art imaging approaches available in our Bioscience Technology Facility will be used to capture the process in action.

This PhD seeks new approaches to BKPyV-specific antiviral therapy driven by greater knowledge of disease-relevant urinary tract biology. Based on the data developed during this studentship we propose to test existing (and/or develop new) pharmacological modulators of the BKPyV-infection biology we observe for future use in 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.