The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways

Rosalind Billharz; Hui Zeng; Sean C Proll; Marcus J Korth; Sharon Lederer; Randy Albrecht; Alan G Goodman; Elizabeth Rosenzweig; Terrence M Tumpey; Adolfo García-Sastre; Michael G Katze

doi:10.1128/JVI.00330-09

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The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways

Journal article

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The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways

Rosalind Billharz, Hui Zeng, Sean C Proll, Marcus J Korth, Sharon Lederer, Randy Albrecht, Alan G Goodman, Elizabeth Rosenzweig, Terrence M Tumpey, Adolfo García-Sastre, …

Journal of virology, Vol.83(20), pp.10557-10570

10/2009

DOI: https://doi.org/10.1128/JVI.00330-09

Handle:

https://hdl.handle.net/2376/106420

PMCID: PMC2753112

PMID: 19706713

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https://doi.org/10.1128/JVI.00330-09View

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Abstract

Influenza A Virus, H1N1 Subtype - immunology

Oligonucleotide Array Sequence Analysis

Humans

Influenza A virus - genetics

Gene Expression Profiling

Lung - cytology

Recombinant Fusion Proteins - metabolism

Lung - virology

Disease Outbreaks

Influenza A virus - pathogenicity

Influenza A virus - immunology

Influenza, Human - virology

Epithelial Cells - cytology

Influenza A Virus, H1N1 Subtype - genetics

Cell Line

Gene Expression Regulation

Viral Plaque Assay

Influenza A Virus, H1N1 Subtype - pathogenicity

Influenza, Human - epidemiology

Interferons - drug effects

Host-Pathogen Interactions

Proteins - genetics

Proteins - metabolism

Epithelial Cells - virology

Lipid Metabolism - drug effects

Interferons - metabolism

Viral Nonstructural Proteins - metabolism

Influenza, Human - immunology

The "Spanish influenza" of 1918 claimed an unprecedented number of lives, yet the determinants of virulence for this virus are still not fully understood. Here, we used functional genomics and an in vitro human lung epithelial cell infection model to define the global host transcriptional response to the eight-gene 1918 virus. To better understand the role of the 1918 virus NS1 gene, we also evaluated the host response to a reassortant 1918 virus containing the NS1 gene from A/Texas/36/91 (a seasonal isolate of human influenza virus), as well as the host response to a reassortant of A/Texas/36/91 containing the 1918 NS1 gene. Genomic analyses revealed that the 1918 virus blocked the transcription of multiple interferon-stimulated genes and also downregulated a network of genes associated with lipid metabolism. In contrast, the expression of genes encoding chemokines and cytokines, which serve to attract infiltrating immune cells, was upregulated. Viruses containing the NS1 gene from A/Texas/36/91 induced a significant increase in type I interferon signaling but did not repress lipid metabolism. The 1918 NS1 gene may therefore have contributed to the virulence of the 1918 pandemic virus by disrupting the innate immune response, inducing hypercytokinemia, and by blocking the transcription of certain lipid-based proinflammatory mediators that function as part of the host antiviral response.

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Title: The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways
Creators: Rosalind Billharz - Department of Microbiology and Washington National Primate Research Center, University of Washington, Seattle, WA 98195-8070, USA
Hui Zeng
Sean C Proll
Marcus J Korth
Sharon Lederer
Randy Albrecht
Alan G Goodman
Elizabeth Rosenzweig
Terrence M Tumpey
Adolfo García-Sastre
Michael G Katze
Publication Details: Journal of virology, Vol.83(20), pp.10557-10570
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: P01 AI058113 / NIAID NIH HHS P01AI058113 / NIAID NIH HHS
Identifiers: 99900546869901842
Language: English
Resource Type: Journal article