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Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression

Tomatidine, a natural steroidal alkaloid from unripe green tomatoes has been shown to exhibit many health benefits. We recently provided in vitro evidence that tomatidine reduces the infectivity of Dengue virus (DENV) and Chikungunya virus (CHIKV), two medically important arthropod-borne human infec...

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Autores principales: Troost-Kind, Berit, van Hemert, Martijn J., van de Pol, Denise, van der Ende-Metselaar, Heidi, Merits, Andres, Borggrewe, Malte, Rodenhuis-Zybert, Izabela A., Smit, Jolanda M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664216/
https://www.ncbi.nlm.nih.gov/pubmed/34762680
http://dx.doi.org/10.1371/journal.pntd.0009916
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author Troost-Kind, Berit
van Hemert, Martijn J.
van de Pol, Denise
van der Ende-Metselaar, Heidi
Merits, Andres
Borggrewe, Malte
Rodenhuis-Zybert, Izabela A.
Smit, Jolanda M.
author_facet Troost-Kind, Berit
van Hemert, Martijn J.
van de Pol, Denise
van der Ende-Metselaar, Heidi
Merits, Andres
Borggrewe, Malte
Rodenhuis-Zybert, Izabela A.
Smit, Jolanda M.
author_sort Troost-Kind, Berit
collection PubMed
description Tomatidine, a natural steroidal alkaloid from unripe green tomatoes has been shown to exhibit many health benefits. We recently provided in vitro evidence that tomatidine reduces the infectivity of Dengue virus (DENV) and Chikungunya virus (CHIKV), two medically important arthropod-borne human infections for which no treatment options are available. We observed a potent antiviral effect with EC50 values of 0.82 μM for DENV-2 and 1.3 μM for CHIKV-LR. In this study, we investigated how tomatidine controls CHIKV infectivity. Using mass spectrometry, we identified that tomatidine induces the expression of p62, CD98, metallothionein and thioredoxin-related transmembrane protein 2 in Huh7 cells. The hits p62 and CD98 were validated, yet subsequent analysis revealed that they are not responsible for the observed antiviral effect. In parallel, we sought to identify at which step of the virus replication cycle tomatidine controls virus infectivity. A strong antiviral effect was seen when in vitro transcribed CHIKV RNA was transfected into Huh7 cells treated with tomatidine, thereby excluding a role for tomatidine during CHIKV cell entry. Subsequent determination of the number of intracellular viral RNA copies and viral protein expression levels during natural infection revealed that tomatidine reduces the RNA copy number and viral protein expression levels in infected cells. Once cells are infected, tomatidine is not able to interfere with active RNA replication yet it can reduce viral protein expression. Collectively, the results delineate that tomatidine controls viral protein expression to exert its antiviral activity. Lastly, sequential passaging of CHIKV in presence of tomatidine did not lead to viral resistance. Collectively, these results further emphasize the potential of tomatidine as an antiviral treatment towards CHIKV infection.
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spelling pubmed-86642162021-12-11 Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression Troost-Kind, Berit van Hemert, Martijn J. van de Pol, Denise van der Ende-Metselaar, Heidi Merits, Andres Borggrewe, Malte Rodenhuis-Zybert, Izabela A. Smit, Jolanda M. PLoS Negl Trop Dis Research Article Tomatidine, a natural steroidal alkaloid from unripe green tomatoes has been shown to exhibit many health benefits. We recently provided in vitro evidence that tomatidine reduces the infectivity of Dengue virus (DENV) and Chikungunya virus (CHIKV), two medically important arthropod-borne human infections for which no treatment options are available. We observed a potent antiviral effect with EC50 values of 0.82 μM for DENV-2 and 1.3 μM for CHIKV-LR. In this study, we investigated how tomatidine controls CHIKV infectivity. Using mass spectrometry, we identified that tomatidine induces the expression of p62, CD98, metallothionein and thioredoxin-related transmembrane protein 2 in Huh7 cells. The hits p62 and CD98 were validated, yet subsequent analysis revealed that they are not responsible for the observed antiviral effect. In parallel, we sought to identify at which step of the virus replication cycle tomatidine controls virus infectivity. A strong antiviral effect was seen when in vitro transcribed CHIKV RNA was transfected into Huh7 cells treated with tomatidine, thereby excluding a role for tomatidine during CHIKV cell entry. Subsequent determination of the number of intracellular viral RNA copies and viral protein expression levels during natural infection revealed that tomatidine reduces the RNA copy number and viral protein expression levels in infected cells. Once cells are infected, tomatidine is not able to interfere with active RNA replication yet it can reduce viral protein expression. Collectively, the results delineate that tomatidine controls viral protein expression to exert its antiviral activity. Lastly, sequential passaging of CHIKV in presence of tomatidine did not lead to viral resistance. Collectively, these results further emphasize the potential of tomatidine as an antiviral treatment towards CHIKV infection. Public Library of Science 2021-11-11 /pmc/articles/PMC8664216/ /pubmed/34762680 http://dx.doi.org/10.1371/journal.pntd.0009916 Text en © 2021 Troost-Kind et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Troost-Kind, Berit
van Hemert, Martijn J.
van de Pol, Denise
van der Ende-Metselaar, Heidi
Merits, Andres
Borggrewe, Malte
Rodenhuis-Zybert, Izabela A.
Smit, Jolanda M.
Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title_full Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title_fullStr Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title_full_unstemmed Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title_short Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression
title_sort tomatidine reduces chikungunya virus progeny release by controlling viral protein expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664216/
https://www.ncbi.nlm.nih.gov/pubmed/34762680
http://dx.doi.org/10.1371/journal.pntd.0009916
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