Cargando…

Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo

HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the peripher...

Descripción completa

Detalles Bibliográficos
Autores principales: Singh, Pankaj, Collins, Matthew F., Johns, Richard N., Manuel, Kayley A., Ye, Ziyun A., Bloom, David C., Neumann, Donna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144644/
https://www.ncbi.nlm.nih.gov/pubmed/35632655
http://dx.doi.org/10.3390/v14050909
_version_ 1784716098448392192
author Singh, Pankaj
Collins, Matthew F.
Johns, Richard N.
Manuel, Kayley A.
Ye, Ziyun A.
Bloom, David C.
Neumann, Donna M.
author_facet Singh, Pankaj
Collins, Matthew F.
Johns, Richard N.
Manuel, Kayley A.
Ye, Ziyun A.
Bloom, David C.
Neumann, Donna M.
author_sort Singh, Pankaj
collection PubMed
description HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5′exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery.
format Online
Article
Text
id pubmed-9144644
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91446442022-05-29 Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo Singh, Pankaj Collins, Matthew F. Johns, Richard N. Manuel, Kayley A. Ye, Ziyun A. Bloom, David C. Neumann, Donna M. Viruses Article HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5′exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery. MDPI 2022-04-27 /pmc/articles/PMC9144644/ /pubmed/35632655 http://dx.doi.org/10.3390/v14050909 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
Singh, Pankaj
Collins, Matthew F.
Johns, Richard N.
Manuel, Kayley A.
Ye, Ziyun A.
Bloom, David C.
Neumann, Donna M.
Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title_full Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title_fullStr Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title_full_unstemmed Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title_short Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo
title_sort deletion of the ctrl2 insulator in hsv-1 results in the decreased expression of genes involved in axonal transport and attenuates reactivation in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144644/
https://www.ncbi.nlm.nih.gov/pubmed/35632655
http://dx.doi.org/10.3390/v14050909
work_keys_str_mv AT singhpankaj deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT collinsmatthewf deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT johnsrichardn deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT manuelkayleya deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT yeziyuna deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT bloomdavidc deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo
AT neumanndonnam deletionofthectrl2insulatorinhsv1resultsinthedecreasedexpressionofgenesinvolvedinaxonaltransportandattenuatesreactivationinvivo