Abstract
Human disease caused by highly pathogenic avian influenza (HPAI) H5N1 can lead to a rapidly progressive viral pneumonia leading to acute respiratory distress syndrome. There is increasing evidence from clinical, animal models and in vitro data, which suggests a role for virus-induced cytokine dysregulation in contributing to the pathogenesis of human H5N1 disease. The key target cells for the virus in the lung are the alveolar epithelium and alveolar macrophages, and we have shown that, compared to seasonal human influenza viruses, equivalent infecting doses of H5N1 viruses markedly up-regulate pro-inflammatory cytokines in both primary cell types in vitro. Whether this H5N1-induced dysregulation of host responses is driven by qualitative (i.e activation of unique host pathways in response to H5N1) or quantitative differences between seasonal influenza viruses is unclear. Here we used microarrays to analyze and compare the gene expression profiles in primary human macrophages at 1, 3, and 6 h after infection with H5N1 virus or low-pathogenic seasonal influenza A (H1N1) virus. We found that host responses to both viruses are qualitatively similar with the activation of nearly identical biological processes and pathways. However, in comparison to seasonal H1N1 virus, H5N1 infection elicits a quantitatively stronger host inflammatory response including type I interferon (IFN) and tumor necrosis factor (TNF)-α genes. A network-based analysis suggests that the synergy between IFN-β and TNF-α results in an enhanced and sustained IFN and pro-inflammatory cytokine response at the early stage of viral infection that may contribute to the viral pathogenesis and this is of relevance to the design of novel therapeutic strategies for H5N1 induced respiratory disease.
Highlights
The emergence and spread of the highly pathogenic avian influenza virus (H5N1) in poultry and wild birds with repeated zoonotic transmission to humans has raised concerns about a possible pandemic [1]
We previously found that H5N1 viruses hyper-induce pro-inflammatory cytokines and chemokines in primary human macrophages and alveolar epithelium infected in vitro compared to a similar infecting dose of seasonal H1N1 virus [13,14,15], suggesting that differential host responses initiated by the H5N1 virus may contribute to the pathogenesis of H5N1 viruses in humans
We used the Affymetrix GeneChip Human Gene 1.0 ST array to compare the global gene expression profiles of human macrophages infected with H5N1, H1N1 viruses and mockinfected control cells at 1, 3 and 6 h post-infection
Summary
The emergence and spread of the highly pathogenic avian influenza virus (H5N1) in poultry and wild birds with repeated zoonotic transmission to humans has raised concerns about a possible pandemic [1]. Zoonotic H5N1 disease continues unabated in a number of countries and is likely grossly under-recognised. While a novel H1N1 virus is spreading worldwide and has become pandemic, it remains relatively mild in its severity [2]. Whether arising directly from the avian virus or through reassortment with a current human influenza virus (e.g. novel pandemic H1N1), an H5N1 pandemic remains a possibility. The risk of such an event is low, its potential impact is high, an understanding of the pathogenesis of human H5N1 disease remains a high priority
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
