Abstract
BK polyomavirus (BKPyV) is a ubiquitous pathogen in the human population that is asymptomatic in healthy individuals, but can be life-threatening in those undergoing kidney transplant. To-date, no vaccines or anti-viral therapies are available to treat human BKPyV infections. New therapeutic strategies are urgently required. In this study, using a rational pharmacological screening regimen of known ion channel modulating compounds, we show that BKPyV requires cystic fibrosis transmembrane conductance regulator (CFTR) activity to infect primary renal proximal tubular epithelial cells. Disrupting CFTR function through treatment with the clinically available drug glibenclamide, the CFTR inhibitor CFTR172, or CFTR-silencing, all reduced BKPyV infection. Specifically, time of addition assays and the assessment of the exposure of VP2/VP3 minor capsid proteins indicated a role for CFTR during BKPyV transport to the endoplasmic reticulum, an essential step during the early stages of BKPyV infection. We thus establish CFTR as an important host-factor in the BKPyV life cycle and reveal CFTR modulators as potential anti-BKPyV therapies.
Highlights
BK polyomavirus (BKPyV) was first isolated in 1971 and is a significant risk factor for renal transplant dysfunction and allograft loss (Chong et al, 2019)
To determine if the activity of kidney-expressed channels are required during the BKPyV lifecycle, BKPyV infection assays were performed in the presence of well-characterised modulators of renal K+ channels
Uncontrolled BKPyV replication is responsible for polyomavirus-associated nephropathy (PVAN) and uteric stenosis in kidney transplant patients, and Polyomavirus-associated haemorrhagic cystitis (PVHC) in haematopoietic stem cell transplant recipients
Summary
BK polyomavirus (BKPyV) was first isolated in 1971 and is a significant risk factor for renal transplant dysfunction and allograft loss (Chong et al, 2019). Ion channels regulate many important physiological functions including cell volume, apoptosis, and the ionic homeostasis of intracellular vesicles/organelles (Bardou et al, 2009; Roger et al, 2015; O'Grady and Lee, 2003). These cellular functions frequently overlap with those hijacked during virus infection. We demonstrate that pharmacological blockers of the cystic fibrosis transmembrane conductance regulator (CFTR) impede BKPyV infection in primary kidney cells One of these blockers, glibenclamide, is a clinically approved anti-diabetic drug, revealing a potent FDA approved anti-BKPyV therapeutic. This furthers our understanding of BKPyV infection and replication strategies and reveals new and exciting strategies for much needed anti-BKPyV therapeutics
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