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Title: CELLULAR TRANSCRIPTIONAL PROFILING IN INFLUENZA A VIRUS INFECTED LUNG EPITHELIAL CELLS: THE ROLE OF THE NONSTRUCTURAL NS1 PROTEIN IN THE EVASION OF THE HOST INNATE DEFENSE AND ITS POTENTIAL CONTRIBUTION TO PANDEMIC INFLUENZA

Author
item GEISS, GARY - U OF WA, SEATTLE, WA
item SALVATORE, MIRELLA - MOUNT SANAI, NEW YORK, NY
item Tumpey, Terrence
item CARTER, VICTORIA - U OF WA, SEATTLE, WA
item WANG, XIUYAN - MOUNT SANAI, NEW YORK,NY
item BASLER, CHRISTOPHER - MOUNT SANAI, NEW YORK, NY
item TAUBENBERGER, JEFFERY - ARMED FORCES IN,WASH,DC
item BUMGARNER, ROGER - U OF WA, SEATTLE, WA
item PALESE, PETER - MOUNT SANAI, NEW YORK,NY
item KATZE, MICHAEL - U OF WA, SEATTLE, WA

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Proceedings
Publication Acceptance Date: 7/2/2002
Publication Date: 8/6/2002
Citation: N/A

Interpretive Summary: Influenza viruses are responsible for an average of 20,000 deaths and 114,000 hospitalizations per year. Highly pathogenic strains of influenza A virus have emerged occasionally in recent history producing pandemics such as the one in 1918 that resulted in the death of 20 million people worldwide. Although the mechanism of increased pathogenicity has been genetically traced for a few unusually virulent strains the cause of severe pandemics, such as the one in 1918, and the contribution of individual influenza virus genes to pathogenicity remain largely unknown. DNA microarray technology is increasingly being used to examine the effects of viral infection on host cell gene expression. The advantages of this discovery based approach, is that one can monitor the expression of thousands of genes simultaneously, perhaps identifying co-expressed genes from a single pathway or those that function in multiple pathways. In this work, we use DNA microarray technology to measure the global pattern of cellular gene expression in cells infected influenza. The cellular genes that were differentially regulated by different influenza viruses and the degree of overlap between them were identified using the ResolverÒ Expression Data Analysis System. We conclude from this analysis that one particular gene expression is necessary but most likely not sufficient for evasion of the host innate defenses. Finally, we identified multiple cellular pathways and new potential antiviral genes whose expression is influenced by the presence or absence of specific genes.

Technical Abstract: The NS1 protein of influenza A virus contributes to viral pathogenesis, primarily by enabling the virus to disarm the host cell type interferon defense system. We examined the downstream effects of NS1 protein expression during influenza A virus infection on global cellular mRNA levels by measuring expression of over 13,000 cellular genes in response to infection with wild-type and mutant viruses in human lung epithelial cells. Influenza virus infection resulted in a significant induction of genes involved in the interferon pathway. Deletion of the viral NS1 gene increased the number and magnitude of expression of cellular genes implicated in the interferon and other antiviral pathways. Interestingly, different interferon induced genes showed different sensitivities to NS1 mediated inhibition of their expression. A recombinant virus with a C terminal deletion in its NS1 gene induced an intermediate cellular mRNA expression pattern between wild type and NS1 knockout viruses. Most significantly, a virus containing the 1918 pandemic NS1 gene was more efficient at blocking the expression of interferon regulated genes than its parental influenza virus. Taken together, our results suggests that the cellular response to influenza A virus infection in human lung cells is significantly influenced by the sequence of the NS1 gene demonstrating the importance of the NS1 protein in regulating the host cell response triggered by virus infection.