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Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the New World. No vaccines or antiviral therapies are currently available to prevent or treat hantavirus disease, and gaps in our understanding of how han...

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Autores principales: Kleinfelter, Lara M., Jangra, Rohit K., Jae, Lucas T., Herbert, Andrew S., Mittler, Eva, Stiles, Katie M., Wirchnianski, Ariel S., Kielian, Margaret, Brummelkamp, Thijn R., Dye, John M., Chandran, Kartik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Microbiology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488941/
https://www.ncbi.nlm.nih.gov/pubmed/26126854
http://dx.doi.org/10.1128/mBio.00801-15
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author Kleinfelter, Lara M.
Jangra, Rohit K.
Jae, Lucas T.
Herbert, Andrew S.
Mittler, Eva
Stiles, Katie M.
Wirchnianski, Ariel S.
Kielian, Margaret
Brummelkamp, Thijn R.
Dye, John M.
Chandran, Kartik
author_facet Kleinfelter, Lara M.
Jangra, Rohit K.
Jae, Lucas T.
Herbert, Andrew S.
Mittler, Eva
Stiles, Katie M.
Wirchnianski, Ariel S.
Kielian, Margaret
Brummelkamp, Thijn R.
Dye, John M.
Chandran, Kartik
author_sort Kleinfelter, Lara M.
collection PubMed
description Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the New World. No vaccines or antiviral therapies are currently available to prevent or treat hantavirus disease, and gaps in our understanding of how hantaviruses enter cells challenge the search for therapeutics. We performed a haploid genetic screen in human cells to identify host factors required for entry by Andes virus, a highly virulent New World hantavirus. We found that multiple genes involved in cholesterol sensing, regulation, and biosynthesis, including key components of the sterol response element-binding protein (SREBP) pathway, are critical for Andes virus entry. Genetic or pharmacological disruption of the membrane-bound transcription factor peptidase/site-1 protease (MBTPS1/S1P), an SREBP control element, dramatically reduced infection by virulent hantaviruses of both the Old World and New World clades but not by rhabdoviruses or alphaviruses, indicating that this pathway is broadly, but selectively, required by hantaviruses. These results could be fully explained as arising from the modest depletion of cellular membrane cholesterol that accompanied S1P disruption. Mechanistic studies of cells and with protein-free liposomes suggested that high levels of cholesterol are specifically needed for hantavirus membrane fusion. Taken together, our results indicate that the profound dependence on target membrane cholesterol is a fundamental, and unusual, biophysical property of hantavirus glycoprotein-membrane interactions during entry.
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spelling pubmed-44889412015-07-07 Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion Kleinfelter, Lara M. Jangra, Rohit K. Jae, Lucas T. Herbert, Andrew S. Mittler, Eva Stiles, Katie M. Wirchnianski, Ariel S. Kielian, Margaret Brummelkamp, Thijn R. Dye, John M. Chandran, Kartik mBio Research Article Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the New World. No vaccines or antiviral therapies are currently available to prevent or treat hantavirus disease, and gaps in our understanding of how hantaviruses enter cells challenge the search for therapeutics. We performed a haploid genetic screen in human cells to identify host factors required for entry by Andes virus, a highly virulent New World hantavirus. We found that multiple genes involved in cholesterol sensing, regulation, and biosynthesis, including key components of the sterol response element-binding protein (SREBP) pathway, are critical for Andes virus entry. Genetic or pharmacological disruption of the membrane-bound transcription factor peptidase/site-1 protease (MBTPS1/S1P), an SREBP control element, dramatically reduced infection by virulent hantaviruses of both the Old World and New World clades but not by rhabdoviruses or alphaviruses, indicating that this pathway is broadly, but selectively, required by hantaviruses. These results could be fully explained as arising from the modest depletion of cellular membrane cholesterol that accompanied S1P disruption. Mechanistic studies of cells and with protein-free liposomes suggested that high levels of cholesterol are specifically needed for hantavirus membrane fusion. Taken together, our results indicate that the profound dependence on target membrane cholesterol is a fundamental, and unusual, biophysical property of hantavirus glycoprotein-membrane interactions during entry. American Society of Microbiology 2015-06-30 /pmc/articles/PMC4488941/ /pubmed/26126854 http://dx.doi.org/10.1128/mBio.00801-15 Text en Copyright © 2015 Kleinfelter et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kleinfelter, Lara M.
Jangra, Rohit K.
Jae, Lucas T.
Herbert, Andrew S.
Mittler, Eva
Stiles, Katie M.
Wirchnianski, Ariel S.
Kielian, Margaret
Brummelkamp, Thijn R.
Dye, John M.
Chandran, Kartik
Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title_full Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title_fullStr Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title_full_unstemmed Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title_short Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion
title_sort haploid genetic screen reveals a profound and direct dependence on cholesterol for hantavirus membrane fusion
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488941/
https://www.ncbi.nlm.nih.gov/pubmed/26126854
http://dx.doi.org/10.1128/mBio.00801-15
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