A Conserved Residue, Tyrosine (Y) 84, in H5N1 Influenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection

Viruses
Ben Xuhao WangEleanor N Fish

Abstract

The non-structural protein, NS1, is a virulence factor encoded by influenza A viruses (IAVs). In this report, we provide evidence that the conserved residue, tyrosine (Y) 84, in a conserved putative SH2-binding domain in A/Duck/Hubei/2004/L-1 [H5N1] NS1 is critical for limiting an interferon (IFN) response to infection. A phenylalanine (F) substitution of this Y84 residue abolishes NS1-mediated downregulation of IFN-inducible STAT phosphorylation, and surface IFNAR1 expression. Recombinant IAV (rIAV) [H1N1] expressing A/Grey Heron/Hong Kong/837/2004 [H5N1] NS1-Y84F (rWSN-GH-NS1-Y84F) replicates to lower titers in human lung epithelial cells and is more susceptible to the antiviral effects of IFN-β treatment compared with rIAV expressing the intact H5N1 NS1 (rWSN-GH-NS1-wt). Cells infected with rWSN-GH-NS1-Y84F express higher levels of IFN stimulated genes (ISGs) associated with an antiviral response compared with cells infected with rWSN-GH-NS1-wt. In mice, intranasal infection with rWSN-GH-NS1-Y84F resulted in a delay in onset of weight loss, reduced lung pathology, lower lung viral titers and higher ISG expression, compared with mice infected with rWSN-GH-NS1-wt. IFN-β treatment of mice infected with rWSN-GH-NS1-Y84F reduced ...Continue Reading

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Citations

Apr 16, 2018·Neuronal Signaling·Laura K OlsenDeclan P McKernan
Nov 5, 2020·Journal of Virology·Javier Gutierrez-AlvarezLuis Enjuanes
Nov 28, 2019·Seminars in Immunology·Ben X Wang, Eleanor N Fish
Mar 30, 2021·Frontiers in Pharmacology·Yunlian ZhouJie Zhu
May 7, 2021·Neuronal Signaling·Eilis Dowd, Declan P McKernan
Jul 31, 2021·Frontiers in Cellular and Infection Microbiology·Zhu-Xing JiXiu-Fan Liu

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Methods Mentioned

BETA
Assay
FCS
flow cytometry
enzyme-linked
fluorescence-activated
FACS
nuclear translocation

Software Mentioned

LightCycler Data Analysis
FlowJo
ImageJ
SYBYL
Aperio ImageScope

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