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Title: Genomic profiling of tumor necrosis factor alpha (TNF-alpha) receptor and interleukin-1 receptor knockout mice reveals a link between TNF-alpha signaling and increased severity of 1918 pandemic influenza virus infection

Author
item BELISLE, SARAH - University Of Washington
item TISONCIK, JENNIFER - University Of Washington
item KORTH, MARCUS - University Of Washington
item CARTER, VICTORIA - University Of Washington
item PROLL, SEAN - University Of Washington
item Swayne, David
item Pantin Jackwood, Mary
item TUMPEY, TERRENCE - Centers For Disease Control And Prevention (CDC) - United States
item KATZE, MICHAEL - University Of Washington

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2010
Publication Date: 12/1/2010
Citation: Belisle, S.E., Tisoncik, J.R., Korth, M.J., Carter, V.S., Proll, S.C., Swayne, D.E., Pantin-Jackwood, M.J., Tumpey, T.M., Katze, M.G. 2010. Genomic profiling of tumor necrosis factor alpha (TNF-alpha) receptor and interleukin-1 receptor knockout mice reveals a link between TNF-alpha signaling and increased severity of 1918 pandemic influenza virus infection. Journal of Virology. 84(24):12576-12588. DOI: 10.1128/JVI.01310-10.

Interpretive Summary: The 1918 Spanish influenza pandemic caused human illness and deaths through abnormal host response, mainly via exaggerated inflammatory chemical (cytokine) response. To understand how illness and death are produced, mouse models were studied with deficient immune responses. In TNFRKO mice, we found delayed or decreased expression of genes associated with antiviral and innate immune signaling, complement, coagulation, and negative acute-phase response. In contrast, in IL1RKO mice numerous genes were increased for the expression of genes that contribute to dendritic and natural killer cell processes and cellular movement. We also observed a compensatory increase in TNF-alpha expression in virus-infected IL1RKO mice. Our data suggest that signaling through the IL-1 receptor is protective whereas signaling through the TNF-alpha receptor increases the severity of 1918 virus infection. These findings suggest that manipulation of these pathways may have therapeutic benefit.

Technical Abstract: The influenza pandemic of 1918-1919 was one of the worst global pandemics in recent history. The highly pathogenic nature of the 1918 virus is thought to be mediated in part by a dysregulation of the host response, including an exacerbated pro-inflammatory cytokine response. In the present study, we compared the host transcriptional response to infection with the reconstructed 1918 virus in wild type, TNF-receptor-1 knockout (TNFRKO), and IL-1-receptor-1 knockout (IL1RKO) mice as a means of further understanding the role of pro-inflammatory cytokine signaling during the acute response to infection. Despite reported redundancy in the functions of IL-1beta and TNF-alpha, we observed that reducing the signaling capacity of each of these molecules by genetic disruption of their key receptor genes had very different effects on the host response to infection. In TNFRKO mice, we found delayed or decreased expression of genes associated with antiviral and innate immune signaling, complement, coagulation, and negative acute-phase response. In contrast, in IL1RKO mice numerous genes were differentially expressed at 1 dpi, including an increase in the expression of genes that contribute to dendritic (DC) and natural killer (NK) cell processes and cellular movement, and gene expression profiles remained relatively constant at later time points. We also observed a compensatory increase in TNF-alpha expression in virus-infected IL1RKO mice. Our data suggest that signaling through the IL-1 receptor is protective whereas signaling through the TNF-alpha receptor increases the severity of 1918 virus infection. These findings suggest that manipulation of these pathways may have therapeutic benefit.