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.
The NS1 protein of influenza A virus contributes to viral pathogenesis, primarily by enabling the virus to disarm the host cell type IFN 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 A/PR/8/34 virus infection resulted in a significant induction of genes involved in the IFN pathway. Deletion of the viral NS1 gene increased the number and magnitude of expression of cellular genes implicated in the IFN, NF-kappaB, and other antiviral pathways. Interestingly, different IFN-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 IFN-regulated genes than its parental influenza A/WSN/33 virus. Taken together, our results suggest 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.
Geiss
Gary K
GK
Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Salvatore
Mirella
M
Tumpey
Terrence M
TM
Carter
Victoria S
VS
Wang
Xiuyan
X
Basler
Christopher F
CF
Taubenberger
Jeffery K
JK
Bumgarner
Roger E
RE
Palese
Peter
P
Katze
Michael G
MG
García-Sastre
Adolfo
A
D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D007251:Influenza, Human / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics; D008168:Lung; D016328:NF-kappa B / Q000276:immunology; D014158:Transcription, Genetic; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*
C085820:INS1 protein, influenza virus; D016328:NF-kappa B; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta