Date Published: December 14, 2009
Publisher: Public Library of Science
Author(s): Suki M. Y. Lee, Jennifer L. Gardy, C. Y. Cheung, Timothy K. W. Cheung, Kenrie P. Y. Hui, Nancy Y. Ip, Y. Guan, Robert E. W. Hancock, J. S. Malik Peiris, Stefan Bereswill. http://doi.org/10.1371/journal.pone.0008072
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.
Partial Text: 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 . Zoonotic H5N1 disease continues unabated in a number of countries and is likely grossly under-recognised. At the time of writing, 440 human cases have been reported with 262 fatalities, an overall case fatality rate of approximately 60% (Cumulative Number of Confirmed Human Cases of Avian Influenza A/H5N1 reported to World Health Organization). While a novel H1N1 virus is now spreading worldwide and has become pandemic, it remains relatively mild in its severity . Given its origin from influenza viruses of swine , , there is a concern that this virus will become epizootic in pigs, similar to the 1918 pandemic H1N1 virus . If so, there will be many opportunities for the pandemic H1N1 to reassort with avian H5N1, which has repeatedly been isolated from pigs . 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. Although the risk of such an event is low, its potential impact is high, thus an understanding of the pathogenesis of human H5N1 disease remains a high priority.
To elucidate the mechanisms of pathogenesis of highly pathogenic avian influenza H5N1 in humans, we identified here the commonalities and differences of host-response signaling pathways in primary human macrophages infected with highly pathogenic influenza A/Vietnam/3212/2004 (H5N1) compared to a low-pathogenicity seasonal human influenza A/Hong Kong/54/1998 (H1N1). These two viruses were selected as they are representative of HPAI H5N1 and seasonal human influenza viruses in general with respect to cytokine phenotype . We carried out a comprehensive microarray study to compare the host responses of H5N1- and H1N1-infected primary human macrophages at different stages of the viral replication cycle (1, 3 and 6 h post-infection).