Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection

Authors: CILLONIZ, CRISTIAN - University Of Washington; Pantin Jackwood, Mary; NI, CHESTER - University Of Washington; GOODMAN, ALAN - University Of Washington; PENG, XINXIA - University Of Washington; PROLL, SEAN - University Of Washington; CARTER, VICTORIA - University Of Washington; ROSENZWEIG, ELIZABETH - University Of Washington; SZRETTER, KRISTY - Centers For Disease Control And Prevention (CDC) - United States; KATZ, JACQUELINE - Centers For Disease Control And Prevention (CDC) - United States; KORTH, MARCUS - University Of Washington; Swayne, David; TUMPEY, TERRENCE - Centers For Disease Control And Prevention (CDC) - United States; KATZE, MICHAEL - University Of Washington

Submitted to: Options for the Control of Influenza Conference
Publication Type: Abstract Only
Publication Acceptance Date: 7/15/2010
Publication Date: 9/3/2010
Citation: Cilloniz, C., Pantin Jackwood, M.J., Ni, C., Goodman, A.G., Peng, X., Proll, S.C., Carter, V.S., Rosenzweig, E.R., Szretter, K.J., Katz, J.M., Korth, M.J., Swayne, D.E., Tumpey, T.M., Katze, M.G. 2010. Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection [abstract]. Options for the Control of Influenza Conference, September 3-7, 2010, Hong Kong, SAR China. p. 335.

Interpretive Summary:

Technical Abstract: Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses, and the current H1N1 pandemic, highlight the need for a more detailed understanding of influenza virus pathogenesis. The continued emergence of new influenza viruses highlights the need to better understand influenza virus-host interactions and mechanisms of pathogenicity. Such an understanding is necessary to facilitate the development of safe and effective therapeutics and vaccines, critical aspects of preparedness for the current and future pandemics. Here, we sought to compare the host transcriptional response to the reconstructed 1918 virus and the avian H5N1 virus Vietnam/1203/04 (VN/1203), with the goal of gaining insights into the underlying mechanisms that make these viruses so lethal. To investigate the host transcriptional response induced by pathogenic influenza viruses we used a functional genomics approach to compare gene expression profiles in lungs from wild-type SvEv129 (129S6/SvEv) mice with two animals/time point for 1918 virus-infected mice (24 animals total) or three animals/time point for VN/1203-infected mice (36 animals total). Global gene expression in infected lungs was compared to genetic match mock control RNA for each group prepared from a pool of equal masses of total RNA from lung tissue of three uninfected mice. Additional findings were obtained from IFNR1-alpha/Beta receptor deficient (IFNR1-/-) mice and mouse embryonic fibroblasts derived from these animals as well as uninfected 129S6/SvEv (6 animals) and IFNR1-/- mice (6 animals) intranasally treated with 10,000 units of recombinant human IFN-alpha A/D. Although both viruses reached similar titers in the lung and caused a lethal infection, the mean time of death was 6 days for VN/1203-infected animals and 9 days for mice infected with the 1918 virus. VN/1203-infected animals also exhibited an earlier and more potent inflammatory response. This response included induction of genes encoding components of the inflammasome. VN/1203 was also able to disseminate to multiple organs, including the brain, which correlated with changes in the expression of genes associated with hematological functions and lipoxin biogenesis and signaling. Both viruses elicited expression of type I interferon (IFN)-regulated genes in wild-type mice and to a lesser extent in mice lacking the type I IFN receptor, suggesting alternative or redundant pathways for IFN signaling. These results clearly indicate a significant difference in the host response to the H1N1 1918 virus and the avian H5N1 VN/1203 virus and correlated well with our mouse microarray data. The combination of a stronger inflammatory and type I IFN response induced by VN/1203 virus likely contribute to the increased pathogenesis of this virus in the mouse model. Taken together, our results suggest that VN/1203-infected mice died faster likely as a consequence of several factors: 1) the early and sustained induction of an inflammatory response that may be detrimental rather than protective to the host, 2) the additive and/or synergistic effects of the viral sensing (TLRs and RIG-I), modulators (chemokines, NF-kappa/Beta, IFN), and effector (PKR, neutrophil infiltration, inflammation) components of the immune response, which were transcriptionally induced in a steady manner throughout infection, 3) the inhibition of lipoxin-mediated anti-inflammatory responses, and 4) the ability of VN/1203 to disseminate to extrapulmonary organs. Consolidation of our data from macaque and mouse infection studies suggests that the early and sustained up-regulation of the inflammatory response is detrimental to the host. Together, our findings highlight the importance of the inflammatory response and suggest new lines of experimentation, including the infection of inflammasome knockout mice and specific targeting of the Alox5 gene responsible for lipoxin b