Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/19/2010
Publication Date: 5/26/2010
Publication URL: http://handle.nal.usda.gov/10113/60775
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. Journal of Virology. 84(15):7613-7624. DOI: 10.1128/JVI.00553-10. Interpretive Summary: The 1918 Spanish influenza pandemic, H5N1 highly pathogenic avian influenza (HPAI) viruses, and the current pandemic H1N1 (2009) have caused human illness and deaths. To understand how illness and death are produced, a mouse model was studied with all three types of viruses. The H5N1 HPAI caused more severe illness and earlier death than 1918 virus and spread throughout the body causing infections. The H5N1 HPAI virus induced early host gene response than the 1918 virus with many of the responses being involved in early and sustained inflammatory processes, and the ability to spread to multiple organs.
Technical Abstract: Lessons learned from the Spanish influenza pandemic, the periodic outbreaks of highly pathogenic avian H5N1 influenza viruses, and the current H1N1 ("swine flu") pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis and the host response to infection. To investigate the host transcriptional response against highly pathogenic influenza viruses in a mouse model that resembles human influenza pathogenicity, we used a functional genomics approach to compare transcriptional profiles in lungs from wild-type 129S6/SvEv mice infected with either the fully reconstructed human H1N1 1918 "Spanish influenza" virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). In the mouse model, VN/1203 was more pathogenic than the 1918 virus and was able to disseminate to brain and spleen, however 1918 virus did not disseminate. Dissemination was not due to virus growth, as evidenced by the similarity in viral titers. Mice succumbed to both viral infections, but VN/1203-infected mice died faster than 1918-infected animals. These findings suggest a remarkable difference in the pathogenicity of these viruses. At day 1 post infection, VN/1203 induced a stronger expression of immune response genes compared to the 1918 virus; the later virus induced a delay host gene expression. Furthermore, one of the top functions differentially regulated by VN/1203 infection was the inflammatory response, which included inflammasome components and potent inflammatory molecules. Both VN/1203 and 1918 infections elicited the expression of type I interferon related genes in wild-type, interferon-a/ß receptor-deficient (IFNR1-/-) mice and mouse embryonic fibroblasts (MEFs), although expression with VN/1203 was more robust. Remarkably, we found that dissemination of the VN/1203 virus in wild-type animals was associated with differential regulation of hematological function and inhibitory effect of lipoxins. Our findings suggest that VN/1203-infected mice died faster than 1918-infected mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of up-regulated components of the immune response, inhibition of the lipoxin-mediated anti-inflammatory responses, and the innate ability of VN/1203 to disseminate to extrapulmonary organs and to generate tissue damage at these sites.