Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level

Konrad Stadler, Huy Riem Ha, Vincenzo Ciminale, Carlo Spirli, Giulietta Saletti, Marco Schiavon, Daniela Bruttomesso, Laurent Bigler, Ferenc Follath, Andrea Pettenazzo, Aldo Baritussio

Research output: Contribution to journalArticle

Abstract

Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear. Our objective was to study amiodarone uptake, clarify the origin of vacuoles, and investigate the effect of amiodarone on the life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of 125I-amiodarone and 125I-B2, an analog lacking the lateral group diethylamino-β- ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus. We found that (1) amiodarone associates with different cell membranes and accumulates in acidic organelles; (2) the diethylamino-β- ethoxy group is an important determinant of uptake; (3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes; (4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and (5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS coronavirus infection by acting after the transit of the virus through endosomes.

Original languageEnglish
Pages (from-to)142-149
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume39
Issue number2
DOIs
Publication statusPublished - Aug 1 2008

Keywords

  • Amiodarone
  • Endocytic pathway
  • SARS coronavirus

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology

Fingerprint Dive into the research topics of 'Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level'. Together they form a unique fingerprint.

  • Cite this

    Stadler, K., Ha, H. R., Ciminale, V., Spirli, C., Saletti, G., Schiavon, M., Bruttomesso, D., Bigler, L., Follath, F., Pettenazzo, A., & Baritussio, A. (2008). Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level. American Journal of Respiratory Cell and Molecular Biology, 39(2), 142-149. https://doi.org/10.1165/rcmb.2007-0217OC