Multifunctional adaptive NS1 mutations are selected upon human influenza virus evolution in the mouse.

PloS One
Nicole E ForbesEarl G Brown

Abstract

The role of the NS1 protein in modulating influenza A virulence and host range was assessed by adapting A/Hong Kong/1/1968 (H3N2) (HK-wt) to increased virulence in the mouse. Sequencing the NS genome segment of mouse-adapted variants revealed 11 mutations in the NS1 gene and 4 in the overlapping NEP gene. Using the HK-wt virus and reverse genetics to incorporate mutant NS gene segments, we demonstrated that all NS1 mutations were adaptive and enhanced virus replication (up to 100 fold) in mouse cells and/or lungs. All but one NS1 mutant was associated with increased virulence measured by survival and weight loss in the mouse. Ten of twelve NS1 mutants significantly enhanced IFN-β antagonism to reduce the level of IFN β production relative to HK-wt in infected mouse lungs at 1 day post infection, where 9 mutants induced viral yields in the lung that were equivalent to or significantly greater than HK-wt (up to 16 fold increase). Eight of 12 NS1 mutants had reduced or lost the ability to bind the 30 kDa cleavage and polyadenylation specificity factor (CPSF30) thus demonstrating a lack of correlation with reduced IFN β production. Mutant NS1 genes resulted in increased viral mRNA transcription (10 of 12 mutants), and protein produ...Continue Reading

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Citations

Sep 15, 2012·BMC Medicine·Sailen Barik
May 16, 2015·PloS One·Woo-Chang ChungMoon Jung Song
May 29, 2014·Journal of Lipid Research·Lukas Bahati TannerMarkus R Wenk
Sep 8, 2018·Viruses·Rachel Emily Levene, Marta Maria Gaglia

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Datasets Mentioned

BETA
CY033549
JN896299

Methods Mentioned

BETA
ELISA
pulldown
pull-down
electrophoresis
pulldowns
PCR
PhosphorScreen
light microscopy
Assay
pull down

Software Mentioned

Imagequant
Excel
GraphPad Prism
Adobe Photoshop
it
GE Imagequant
UNScan

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