Glibenclamide inhibits BK polyomavirus infection in kidney cells through CFTR blockade
| Autor: | Ethan L. Morgan, Eleni-Anna Loundras, Margarita-Maria Panou, Jamel Mankouri, Matthew Welberry-Smith, Christopher W. Wasson, Andrew Macdonald, Michelle Antoni |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities 030106 microbiology Population Cystic Fibrosis Transmembrane Conductance Regulator PVAN medicine.disease_cause Virus Replication Antiviral Agents Article Glibenclamide Kidney Tubules Proximal 03 medical and health sciences BK virus KATP Channels Virology Glyburide Potassium Channel Blockers Medicine Humans CFTR education Pathogen Cells Cultured Pharmacology education.field_of_study Kidney biology business.industry Endoplasmic reticulum Cystic fibrosis transmembrane conductance regulator Blockade 030104 developmental biology medicine.anatomical_structure Cancer research biology.protein Capsid Proteins Urothelium business Ion channel medicine.drug |
| Zdroj: | Antiviral Research |
| ISSN: | 1872-9096 0166-3542 |
| Popis: | 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) is life-threatening in those undergoing kidney transplant. • BKPyV requires CFTR to infect primary kidney cells. • Disrupting CFTR function pharmacologically reduces BKPyV infection. • CFTR is required during BKPyV transport to the endoplasmic reticulum. |
| Databáze: | OpenAIRE |
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