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Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection
Open accessAbstract
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. 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 129S6/SvEv mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Although the viruses reached similar titers in the lung and caused lethal infections, 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. Our findings suggest that VN/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of upregulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/1203 to disseminate to extrapulmonary organs.
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“Cytokine signaling pathway redundancy is also observed with respect to type I IFN signaling, as there is strong upregulation of IFN-stimulated gene expression in IFN-␣/R KO mice infected with the 1918 virus (27).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [27]
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Metadata
- Authors
- 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.
- Affiliations
- Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195
- Southeast Poultry Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia 30606
- University of Washington (US)
- Washington University in St. Louis (US)
- Centers for Disease Control and Prevention (US)
- Agricultural Research Service (US)
- Corresponding author
- Katze, Michael G.
- ORCID
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2010-08
- Volume
- 84
- Issue
- 15
- Pages
- 7613-7624
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC2897611
- OpenAlex
- W2130014663
- Cited by
- 136
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 13 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 5 · 2015: 14 · 2014: 8 · 2013: 14 · 2012: 10
- FWCI
- 10.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (P01AI058113)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Keywords
- H5N1 influenza virus, influenza pathogenesis, lung gene expression, inflammation, inflammasome, type I interferon, interferon receptor, viral dissemination, extrapulmonary infection, brain infection, host transcriptional response
- MeSH terms
- Animals, Female, Gene Expression Regulation, Inflammation, Lung, Orthomyxoviridae Infections, Virulence, Signal Transduction, Survival Analysis, Lipoxins, Mice, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H5N1 Subtype
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