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Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism

INTRODUCTION: SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation. METHODS: We used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the...

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Autores principales: Garrett, Timothy J., Coatsworth, Heather, Mahmud, Iqbal, Hamerly, Timothy, Stephenson, Caroline J., Ayers, Jasmine B., Yazd, Hoda S., Miller, Megan R., Lednicky, John A., Dinglasan, Rhoel R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603251/
https://www.ncbi.nlm.nih.gov/pubmed/37901834
http://dx.doi.org/10.3389/fmicb.2023.1251065
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author Garrett, Timothy J.
Coatsworth, Heather
Mahmud, Iqbal
Hamerly, Timothy
Stephenson, Caroline J.
Ayers, Jasmine B.
Yazd, Hoda S.
Miller, Megan R.
Lednicky, John A.
Dinglasan, Rhoel R.
author_facet Garrett, Timothy J.
Coatsworth, Heather
Mahmud, Iqbal
Hamerly, Timothy
Stephenson, Caroline J.
Ayers, Jasmine B.
Yazd, Hoda S.
Miller, Megan R.
Lednicky, John A.
Dinglasan, Rhoel R.
author_sort Garrett, Timothy J.
collection PubMed
description INTRODUCTION: SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation. METHODS: We used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the cells’ autophagic and lipophagic processes as a chemical probe to determine if it can modulate the host cell’s total lipid profile that would otherwise be either amplified or reduced during SARS-CoV-2 infection. RESULTS: Through parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of SARS-CoV-2 infected Vero E6 cells, especially with triglycerides, which were elevated early during virus replication, but decreased thereafter, as well as plasmalogens, which were elevated at later timepoints during virus replication, but were also elevated under normal cell growth. These findings suggested a complex interplay of lipid profile reorganization involving plasmalogen metabolism. We also observed that NIC treatment of both low and high viral loads does not affect virus entry. Instead, NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which we found elevated during virus infection in the absence of NIC, resulting in a significant reduction in the production of infectious virions. Unexpectedly, at higher viral loads, NIC treatment also resulted in elevated triglyceride levels, and induced significant changes in phospholipid metabolism. DISCUSSION: We posit that future screens of approved or new partner drugs should prioritize compounds that effectively counter SARS-CoV-2 subversion of lipid metabolism, thereby reducing virus replication, egress, and the subsequent regulation of key lipid mediators of pathological inflammation.
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spelling pubmed-106032512023-10-28 Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism Garrett, Timothy J. Coatsworth, Heather Mahmud, Iqbal Hamerly, Timothy Stephenson, Caroline J. Ayers, Jasmine B. Yazd, Hoda S. Miller, Megan R. Lednicky, John A. Dinglasan, Rhoel R. Front Microbiol Microbiology INTRODUCTION: SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation. METHODS: We used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the cells’ autophagic and lipophagic processes as a chemical probe to determine if it can modulate the host cell’s total lipid profile that would otherwise be either amplified or reduced during SARS-CoV-2 infection. RESULTS: Through parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of SARS-CoV-2 infected Vero E6 cells, especially with triglycerides, which were elevated early during virus replication, but decreased thereafter, as well as plasmalogens, which were elevated at later timepoints during virus replication, but were also elevated under normal cell growth. These findings suggested a complex interplay of lipid profile reorganization involving plasmalogen metabolism. We also observed that NIC treatment of both low and high viral loads does not affect virus entry. Instead, NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which we found elevated during virus infection in the absence of NIC, resulting in a significant reduction in the production of infectious virions. Unexpectedly, at higher viral loads, NIC treatment also resulted in elevated triglyceride levels, and induced significant changes in phospholipid metabolism. DISCUSSION: We posit that future screens of approved or new partner drugs should prioritize compounds that effectively counter SARS-CoV-2 subversion of lipid metabolism, thereby reducing virus replication, egress, and the subsequent regulation of key lipid mediators of pathological inflammation. Frontiers Media S.A. 2023-10-11 /pmc/articles/PMC10603251/ /pubmed/37901834 http://dx.doi.org/10.3389/fmicb.2023.1251065 Text en Copyright © 2023 Garrett, Coatsworth, Mahmud, Hamerly, Stephenson, Ayers, Yazd, Miller, Lednicky and Dinglasan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Garrett, Timothy J.
Coatsworth, Heather
Mahmud, Iqbal
Hamerly, Timothy
Stephenson, Caroline J.
Ayers, Jasmine B.
Yazd, Hoda S.
Miller, Megan R.
Lednicky, John A.
Dinglasan, Rhoel R.
Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title_full Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title_fullStr Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title_full_unstemmed Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title_short Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism
title_sort niclosamide as a chemical probe for analyzing sars-cov-2 modulation of host cell lipid metabolism
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603251/
https://www.ncbi.nlm.nih.gov/pubmed/37901834
http://dx.doi.org/10.3389/fmicb.2023.1251065
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