Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo

Gregory D. Ebel, Kelly A. Fitzpatrick, Pei Yin Lim, Corey J. Bennett, Eleanor R. Deardorff, Greta V S Jerzak Kramer, Yangsheng Zhou, Pei-Yong Shi, Kristen A. Bernard

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an in vivo fitness assay in Culex quinquefasciatus mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.

Original languageEnglish (US)
Pages (from-to)12605-12613
Number of pages9
JournalJournal of Virology
Volume85
Issue number23
DOIs
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

West Nile virus
Culicidae
pathogenesis
Genome
RNA helicases
RNA Helicases
Viruses
viruses
genome
Infection
infection
RNA Viruses
interferons
Phenotype
phenotype
Birds
Chickens
mice
Population
chickens

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Ebel, G. D., Fitzpatrick, K. A., Lim, P. Y., Bennett, C. J., Deardorff, E. R., Kramer, G. V. S. J., ... Bernard, K. A. (2011). Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo. Journal of Virology, 85(23), 12605-12613. https://doi.org/10.1128/JVI.05637-11

Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo. / Ebel, Gregory D.; Fitzpatrick, Kelly A.; Lim, Pei Yin; Bennett, Corey J.; Deardorff, Eleanor R.; Kramer, Greta V S Jerzak; Zhou, Yangsheng; Shi, Pei-Yong; Bernard, Kristen A.

In: Journal of Virology, Vol. 85, No. 23, 12.2011, p. 12605-12613.

Research output: Contribution to journalArticle

Ebel, GD, Fitzpatrick, KA, Lim, PY, Bennett, CJ, Deardorff, ER, Kramer, GVSJ, Zhou, Y, Shi, P-Y & Bernard, KA 2011, 'Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo', Journal of Virology, vol. 85, no. 23, pp. 12605-12613. https://doi.org/10.1128/JVI.05637-11
Ebel, Gregory D. ; Fitzpatrick, Kelly A. ; Lim, Pei Yin ; Bennett, Corey J. ; Deardorff, Eleanor R. ; Kramer, Greta V S Jerzak ; Zhou, Yangsheng ; Shi, Pei-Yong ; Bernard, Kristen A. / Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo. In: Journal of Virology. 2011 ; Vol. 85, No. 23. pp. 12605-12613.
@article{d5019a865e0541caafd5106d72ca5702,
title = "Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo",
abstract = "West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an in vivo fitness assay in Culex quinquefasciatus mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.",
author = "Ebel, {Gregory D.} and Fitzpatrick, {Kelly A.} and Lim, {Pei Yin} and Bennett, {Corey J.} and Deardorff, {Eleanor R.} and Kramer, {Greta V S Jerzak} and Yangsheng Zhou and Pei-Yong Shi and Bernard, {Kristen A.}",
year = "2011",
month = "12",
doi = "10.1128/JVI.05637-11",
language = "English (US)",
volume = "85",
pages = "12605--12613",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "23",

}

TY - JOUR

T1 - Nonconsensus west nile virus genomes arising during mosquito infection suppress pathogenesis and modulate virus fitness in vivo

AU - Ebel, Gregory D.

AU - Fitzpatrick, Kelly A.

AU - Lim, Pei Yin

AU - Bennett, Corey J.

AU - Deardorff, Eleanor R.

AU - Kramer, Greta V S Jerzak

AU - Zhou, Yangsheng

AU - Shi, Pei-Yong

AU - Bernard, Kristen A.

PY - 2011/12

Y1 - 2011/12

N2 - West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an in vivo fitness assay in Culex quinquefasciatus mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.

AB - West Nile virus (WNV) is similar to other RNA viruses in that it forms genetically complex populations within hosts. The virus is maintained in nature in mosquitoes and birds, with each host type exerting distinct influences on virus populations. We previously observed that prolonged replication in mosquitoes led to increases in WNV genetic diversity and diminished pathogenesis in mice without remarkable changes to the consensus genome sequence. We therefore sought to evaluate the relationships between individual and group phenotypes in WNV and to discover novel viral determinants of pathogenesis in mice and fitness in mosquitoes and birds. Individual plaque size variants were isolated from a genetically complex population, and mutations conferring a small-plaque and mouse-attenuated phenotype were localized to the RNA helicase domain of the NS3 protein by reverse genetics. The mutation, an Asp deletion, did not alter type I interferon production in the host but rendered mutant viruses more susceptible to interferon compared to wild type (WT) WNV. Finally, we used an in vivo fitness assay in Culex quinquefasciatus mosquitoes and chickens to determine whether the mutation in NS3 influenced fitness. The fitness of the NS3 mutant was dramatically lower in chickens and moderately lower in mosquitoes, indicating that RNA helicase is a major fitness determinant of WNV and that the effect on fitness is host specific. Overall, this work highlights the complex relationships that exist between individual and group phenotypes in RNA viruses and identifies RNA helicase as an attenuation and fitness determinant in WNV.

UR - http://www.scopus.com/inward/record.url?scp=81255184273&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81255184273&partnerID=8YFLogxK

U2 - 10.1128/JVI.05637-11

DO - 10.1128/JVI.05637-11

M3 - Article

C2 - 21937657

AN - SCOPUS:81255184273

VL - 85

SP - 12605

EP - 12613

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 23

ER -