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Systems-level comparison of host-responses elicited by avian H5N1 and seasonal
H1N1 influenza viruses in primary human macrophages
#MMPMID20011590
Lee SM
; Gardy JL
; Cheung CY
; Cheung TK
; Hui KP
; Ip NY
; Guan Y
; Hancock RE
; Peiris JS
PLoS One
2009[Dec]; 4
(12
): e8072
PMID20011590
show ga
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)-alpha genes. A network-based analysis suggests that the synergy between
IFN-beta and TNF-alpha 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.
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