RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?

ABSTRACT Flaviviruses include a diverse group of medically important viruses that cycle between mosquitoes and humans. During this natural process of switching hosts, each species imposes different selective forces on the viral population. Using dengue virus (DENV) as model, we found that paralogous...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Luana de Borba, Sergio M. Villordo, Franco L. Marsico, Juan M. Carballeda, Claudia V. Filomatori, Leopoldo G. Gebhard, Horacio M. Pallarés, Sebastian Lequime, Louis Lambrechts, Irma Sánchez Vargas, Carol D. Blair, Andrea V. Gamarnik
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	RNA virus RNA virus evolution RNA-RNA interactions dengue virus flavivirus host adaptation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/850a9c0fbbf54ebc930b23058ee314bc
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:850a9c0fbbf54ebc930b23058ee314bc
record_format	dspace
spelling	oai:doaj.org-article:850a9c0fbbf54ebc930b23058ee314bc2021-11-15T15:55:13ZRNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?10.1128/mBio.02506-182150-7511https://doaj.org/article/850a9c0fbbf54ebc930b23058ee314bc2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02506-18https://doaj.org/toc/2150-7511ABSTRACT Flaviviruses include a diverse group of medically important viruses that cycle between mosquitoes and humans. During this natural process of switching hosts, each species imposes different selective forces on the viral population. Using dengue virus (DENV) as model, we found that paralogous RNA structures originating from duplications in the viral 3′ untranslated region (UTR) are under different selective pressures in the two hosts. These RNA structures, known as dumbbells (DB1 and DB2), were originally proposed to be enhancers of viral replication. Analysis of viruses obtained from infected mosquitoes showed selection of mutations that mapped in DB2. Recombinant viruses carrying the identified variations confirmed that these mutations greatly increase viral replication in mosquito cells, with low or no impact in human cells. Use of viruses lacking each of the DB structures revealed opposite viral phenotypes. While deletion of DB1 reduced viral replication about 10-fold, viruses lacking DB2 displayed a great increase of fitness in mosquitoes, confirming a functional diversification of these similar RNA elements. Mechanistic analysis indicated that DB1 and DB2 differentially modulate viral genome cyclization and RNA replication. We found that a pseudoknot formed within DB2 competes with long-range RNA-RNA interactions that are necessary for minus-strand RNA synthesis. Our results support a model in which a functional diversification of duplicated RNA elements in the viral 3′ UTR is driven by host-specific requirements. This study provides new ideas for understanding molecular aspects of the evolution of RNA viruses that naturally jump between different species. IMPORTANCE Flaviviruses constitute the most relevant group of arthropod-transmitted viruses, including important human pathogens such as the dengue, Zika, yellow fever, and West Nile viruses. The natural alternation of these viruses between vertebrate and invertebrate hosts shapes the viral genome population, which leads to selection of different viral variants with potential implications for epidemiological fitness and pathogenesis. However, the selective forces and mechanisms acting on the viral RNA during host adaptation are still largely unknown. Here, we found that two almost identical tandem RNA structures present at the viral 3′ untranslated region are under different selective pressures in the two hosts. Mechanistic studies indicated that the two RNA elements, known as dumbbells, contain sequences that overlap essential RNA cyclization elements involved in viral RNA synthesis. The data support a model in which the duplicated RNA structures differentially evolved to accommodate distinct functions for viral replication in the two hosts.Luana de BorbaSergio M. VillordoFranco L. MarsicoJuan M. CarballedaClaudia V. FilomatoriLeopoldo G. GebhardHoracio M. PallarésSebastian LequimeLouis LambrechtsIrma Sánchez VargasCarol D. BlairAndrea V. GamarnikAmerican Society for MicrobiologyarticleRNA virusRNA virus evolutionRNA-RNA interactionsdengue virusflavivirushost adaptationMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	RNA virus RNA virus evolution RNA-RNA interactions dengue virus flavivirus host adaptation Microbiology QR1-502
spellingShingle	RNA virus RNA virus evolution RNA-RNA interactions dengue virus flavivirus host adaptation Microbiology QR1-502 Luana de Borba Sergio M. Villordo Franco L. Marsico Juan M. Carballeda Claudia V. Filomatori Leopoldo G. Gebhard Horacio M. Pallarés Sebastian Lequime Louis Lambrechts Irma Sánchez Vargas Carol D. Blair Andrea V. Gamarnik RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
description	ABSTRACT Flaviviruses include a diverse group of medically important viruses that cycle between mosquitoes and humans. During this natural process of switching hosts, each species imposes different selective forces on the viral population. Using dengue virus (DENV) as model, we found that paralogous RNA structures originating from duplications in the viral 3′ untranslated region (UTR) are under different selective pressures in the two hosts. These RNA structures, known as dumbbells (DB1 and DB2), were originally proposed to be enhancers of viral replication. Analysis of viruses obtained from infected mosquitoes showed selection of mutations that mapped in DB2. Recombinant viruses carrying the identified variations confirmed that these mutations greatly increase viral replication in mosquito cells, with low or no impact in human cells. Use of viruses lacking each of the DB structures revealed opposite viral phenotypes. While deletion of DB1 reduced viral replication about 10-fold, viruses lacking DB2 displayed a great increase of fitness in mosquitoes, confirming a functional diversification of these similar RNA elements. Mechanistic analysis indicated that DB1 and DB2 differentially modulate viral genome cyclization and RNA replication. We found that a pseudoknot formed within DB2 competes with long-range RNA-RNA interactions that are necessary for minus-strand RNA synthesis. Our results support a model in which a functional diversification of duplicated RNA elements in the viral 3′ UTR is driven by host-specific requirements. This study provides new ideas for understanding molecular aspects of the evolution of RNA viruses that naturally jump between different species. IMPORTANCE Flaviviruses constitute the most relevant group of arthropod-transmitted viruses, including important human pathogens such as the dengue, Zika, yellow fever, and West Nile viruses. The natural alternation of these viruses between vertebrate and invertebrate hosts shapes the viral genome population, which leads to selection of different viral variants with potential implications for epidemiological fitness and pathogenesis. However, the selective forces and mechanisms acting on the viral RNA during host adaptation are still largely unknown. Here, we found that two almost identical tandem RNA structures present at the viral 3′ untranslated region are under different selective pressures in the two hosts. Mechanistic studies indicated that the two RNA elements, known as dumbbells, contain sequences that overlap essential RNA cyclization elements involved in viral RNA synthesis. The data support a model in which the duplicated RNA structures differentially evolved to accommodate distinct functions for viral replication in the two hosts.
format	article
author	Luana de Borba Sergio M. Villordo Franco L. Marsico Juan M. Carballeda Claudia V. Filomatori Leopoldo G. Gebhard Horacio M. Pallarés Sebastian Lequime Louis Lambrechts Irma Sánchez Vargas Carol D. Blair Andrea V. Gamarnik
author_facet	Luana de Borba Sergio M. Villordo Franco L. Marsico Juan M. Carballeda Claudia V. Filomatori Leopoldo G. Gebhard Horacio M. Pallarés Sebastian Lequime Louis Lambrechts Irma Sánchez Vargas Carol D. Blair Andrea V. Gamarnik
author_sort	Luana de Borba
title	RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
title_short	RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
title_full	RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
title_fullStr	RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
title_full_unstemmed	RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?
title_sort	rna structure duplication in the dengue virus 3′ utr: redundancy or host specificity?
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/850a9c0fbbf54ebc930b23058ee314bc
work_keys_str_mv	AT luanadeborba rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT sergiomvillordo rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT francolmarsico rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT juanmcarballeda rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT claudiavfilomatori rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT leopoldoggebhard rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT horaciompallares rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT sebastianlequime rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT louislambrechts rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT irmasanchezvargas rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT caroldblair rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity AT andreavgamarnik rnastructureduplicationinthedenguevirus3utrredundancyorhostspecificity
_version_	1718427228550725632

RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?

Ejemplares similares