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Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs
Acutely infectious new world alphaviruses such as Venezuelan Equine Encephalitis Virus (VEEV) pose important challenges to the human population due to a lack of effective therapeutic intervention strategies. Small interfering RNAs that can selectively target the viral genome (vsiRNAs) has been obser...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331859/ https://www.ncbi.nlm.nih.gov/pubmed/35893693 http://dx.doi.org/10.3390/v14081628 |
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author | Haikerwal, Amrita Barrera, Michael D. Bhalla, Nishank Zhou, Weidong Boghdeh, Niloufar Anderson, Carol Alem, Farhang Narayanan, Aarthi |
author_facet | Haikerwal, Amrita Barrera, Michael D. Bhalla, Nishank Zhou, Weidong Boghdeh, Niloufar Anderson, Carol Alem, Farhang Narayanan, Aarthi |
author_sort | Haikerwal, Amrita |
collection | PubMed |
description | Acutely infectious new world alphaviruses such as Venezuelan Equine Encephalitis Virus (VEEV) pose important challenges to the human population due to a lack of effective therapeutic intervention strategies. Small interfering RNAs that can selectively target the viral genome (vsiRNAs) has been observed to offer survival advantages in several in vitro and in vivo models of acute virus infections, including alphaviruses such as Chikungunya virus and filoviruses such as Ebola virus. In this study, novel vsiRNAs that targeted conserved regions in the nonstructural and structural genes of the VEEV genome were designed and evaluated for antiviral activity in mammalian cells in the context of VEEV infection. The data demonstrate that vsiRNAs were able to effectively decrease the infectious virus titer at earlier time points post infection in the context of the attenuated TC-83 strain and the virulent Trinidad Donkey strain, while the inhibition was overcome at later time points. Depletion of Argonaute 2 protein (Ago2), the catalytic component of the RISC complex, negated the inhibitory effect of the vsiRNAs, underscoring the involvement of the siRNA pathway in the inhibition process. Depletion of the RNAi pathway proteins Dicer, MOV10, TRBP2 and Matrin 3 decreased viral load in infected cells, alluding to an impact of the RNAi pathway in the establishment of a productive infection. Additional studies focused on rational combinations of effective vsiRNAs and delivery strategies to confer better in vivo bioavailability and distribution to key target tissues such as the brain can provide effective solutions to treat encephalitic diseases resulting from alphavirus infections. |
format | Online Article Text |
id | pubmed-9331859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93318592022-07-29 Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs Haikerwal, Amrita Barrera, Michael D. Bhalla, Nishank Zhou, Weidong Boghdeh, Niloufar Anderson, Carol Alem, Farhang Narayanan, Aarthi Viruses Article Acutely infectious new world alphaviruses such as Venezuelan Equine Encephalitis Virus (VEEV) pose important challenges to the human population due to a lack of effective therapeutic intervention strategies. Small interfering RNAs that can selectively target the viral genome (vsiRNAs) has been observed to offer survival advantages in several in vitro and in vivo models of acute virus infections, including alphaviruses such as Chikungunya virus and filoviruses such as Ebola virus. In this study, novel vsiRNAs that targeted conserved regions in the nonstructural and structural genes of the VEEV genome were designed and evaluated for antiviral activity in mammalian cells in the context of VEEV infection. The data demonstrate that vsiRNAs were able to effectively decrease the infectious virus titer at earlier time points post infection in the context of the attenuated TC-83 strain and the virulent Trinidad Donkey strain, while the inhibition was overcome at later time points. Depletion of Argonaute 2 protein (Ago2), the catalytic component of the RISC complex, negated the inhibitory effect of the vsiRNAs, underscoring the involvement of the siRNA pathway in the inhibition process. Depletion of the RNAi pathway proteins Dicer, MOV10, TRBP2 and Matrin 3 decreased viral load in infected cells, alluding to an impact of the RNAi pathway in the establishment of a productive infection. Additional studies focused on rational combinations of effective vsiRNAs and delivery strategies to confer better in vivo bioavailability and distribution to key target tissues such as the brain can provide effective solutions to treat encephalitic diseases resulting from alphavirus infections. MDPI 2022-07-26 /pmc/articles/PMC9331859/ /pubmed/35893693 http://dx.doi.org/10.3390/v14081628 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Haikerwal, Amrita Barrera, Michael D. Bhalla, Nishank Zhou, Weidong Boghdeh, Niloufar Anderson, Carol Alem, Farhang Narayanan, Aarthi Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title | Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title_full | Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title_fullStr | Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title_full_unstemmed | Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title_short | Inhibition of Venezuelan Equine Encephalitis Virus Using Small Interfering RNAs |
title_sort | inhibition of venezuelan equine encephalitis virus using small interfering rnas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331859/ https://www.ncbi.nlm.nih.gov/pubmed/35893693 http://dx.doi.org/10.3390/v14081628 |
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