In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 15, No. 11 ( 2021-11-11), p. e0009916-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0009916
DOI:
10.1371/journal.pntd.0009916.g001
DOI:
10.1371/journal.pntd.0009916.g002
DOI:
10.1371/journal.pntd.0009916.g003
DOI:
10.1371/journal.pntd.0009916.g004
DOI:
10.1371/journal.pntd.0009916.g005
DOI:
10.1371/journal.pntd.0009916.g006
DOI:
10.1371/journal.pntd.0009916.g007
DOI:
10.1371/journal.pntd.0009916.g008
DOI:
10.1371/journal.pntd.0009916.t001
DOI:
10.1371/journal.pntd.0009916.s001
DOI:
10.1371/journal.pntd.0009916.s002
DOI:
10.1371/journal.pntd.0009916.s003
DOI:
10.1371/journal.pntd.0009916.s004
DOI:
10.1371/journal.pntd.0009916.s005
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2429704-5
