Identification of potassium and calcium channel inhibitors as modulators of polyomavirus endosomal trafficking.
Antiviral Res
; 179: 104819, 2020 07.
Article
in En
| MEDLINE
| ID: mdl-32389733
ABSTRACT
During virus entry, members of the Polyomaviridae transit the endolysosomal network en route to the endoplasmic reticulum (ER), from which degraded capsids escape into the cytoplasm and enter the nucleus. Emerging evidence suggests that viruses require both endosomal acidification and the correct ionic balance of K+ and Ca2+ ions in endosomes for correct virus trafficking and genome release. Here, using two polyomaviruses with different capsid architectures, namely Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we describe methods to rapidly quantify virus infection using IncuCyte ZOOM imaging analysis, and use this system to investigate the role of both K+ and Ca2+ channels during the early stages of virus entry. Using broad spectrum blockers of both K+ and Ca2+ channels to specifically target host cell ion channel functionality, we show that MCPyV, but not SV40 can be inhibited by K+ channel modulators, whilst both viruses are restricted by the broad spectrum Ca2+ channel inhibitor verapamil. Using a panel of more specific Ca2+ blockers, we show that both MCPyV and SV40 are dependent on the activity of two-pore Ca2+ channels (TPCs), as the TPC-specific blocker tetrandrine prevented capsid disassembly and nuclear transport required for virus entry. We therefore reveal a novel target to restrict the entry of polyomaviruses, which given the known role of TPCs during endolysosomal-ER fusion, is likely to be applicable to other viruses that transit this pathway.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Endosomes
/
Calcium Channel Blockers
/
Polyomavirus
/
Potassium Channel Blockers
/
Virus Internalization
Type of study:
Diagnostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Antiviral Res
Year:
2020
Document type:
Article
Affiliation country:
United kingdom
Publication country:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS