Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression.
Animals
Antiviral Agents
/ pharmacology
Cell Line
Chikungunya virus
/ drug effects
Chlorocebus aethiops
Gene Expression
/ drug effects
Humans
Proteomics
RNA, Viral
/ genetics
Tomatine
/ analogs & derivatives
Vero Cells
Viral Proteins
/ genetics
Virus Internalization
/ drug effects
Virus Release
/ drug effects
Virus Replication
/ drug effects
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
18
06
2021
accepted:
16
10
2021
revised:
10
12
2021
pubmed:
12
11
2021
medline:
21
12
2021
entrez:
11
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34762680
doi: 10.1371/journal.pntd.0009916
pii: PNTD-D-21-00897
pmc: PMC8664216
doi:
Substances chimiques
Antiviral Agents
0
RNA, Viral
0
Viral Proteins
0
tomatidine
2B73S48786
Tomatine
31U6547O08
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0009916Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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