Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons

Österlund, Pamela; Pirhonen, Jaana; Ikonen, Niina; Rönkkö, Esa; Strengell, Mari; Mäkelä, Sanna; Broman, Mia; Hamming, Ole J.; Hartmann, Rune; Ziegler, Thedi; Julkunen, Ilkka

doi:10.1128/jvi.01619-09

Cited by 147 publications

(153 citation statements)

References 47 publications

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“…We and others have demonstrated that pdmH1N1 virus does not differ from seasonal influenza viruses in its induction of cytokine responses in human macrophages and epithelial cells [2-4]. This suggests that the cytokine dysregulation seen in H5N1 infection is not an intrinsic feature of the pdmH1N1 virus.…”

Section: Introductionmentioning

confidence: 83%

Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I-like alveolar epithelial cells in vitro

et al. 2010

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BackgroundPandemic influenza H1N1 (pdmH1N1) virus causes mild disease in humans but occasionally leads to severe complications and even death, especially in those who are pregnant or have underlying disease. Cytokine responses induced by pdmH1N1 viruses in vitro are comparable to other seasonal influenza viruses suggesting the cytokine dysregulation as seen in H5N1 infection is not a feature of the pdmH1N1 virus. However a comprehensive gene expression profile of pdmH1N1 in relevant primary human cells in vitro has not been reported. Type I alveolar epithelial cells are a key target cell in pdmH1N1 pneumonia.MethodsWe carried out a comprehensive gene expression profiling using the Affymetrix microarray platform to compare the transcriptomes of primary human alveolar type I-like alveolar epithelial cells infected with pdmH1N1 or seasonal H1N1 virus.ResultsOverall, we found that most of the genes that induced by the pdmH1N1 were similarly regulated in response to seasonal H1N1 infection with respect to both trend and extent of gene expression. These commonly responsive genes were largely related to the interferon (IFN) response. Expression of the type III IFN IL29 was more prominent than the type I IFN IFNβ and a similar pattern of expression of both IFN genes was seen in pdmH1N1 and seasonal H1N1 infection. Genes that were significantly down-regulated in response to seasonal H1N1 but not in response to pdmH1N1 included the zinc finger proteins and small nucleolar RNAs. Gene Ontology (GO) and pathway over-representation analysis suggested that these genes were associated with DNA binding and transcription/translation related functions.ConclusionsBoth seasonal H1N1 and pdmH1N1 trigger similar host responses including IFN-based antiviral responses and cytokine responses. Unlike the avian H5N1 virus, pdmH1N1 virus does not have an intrinsic capacity for cytokine dysregulation. The differences between pdmH1N1 and seasonal H1N1 viruses lay in the ability of seasonal H1N1 virus to down regulate zinc finger proteins and small nucleolar RNAs, which are possible viral transcriptional suppressors and eukaryotic translation initiation factors respectively. These differences may be biologically relevant and may represent better adaptation of seasonal H1N1 influenza virus to the host.

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Section: Introductionmentioning

confidence: 83%

Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I-like alveolar epithelial cells in vitro

et al. 2010

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“…During the first phase of this pandemic, 9 % of patients were hospitalized with pneumonia, respiratory failure or acute respiratory distress syndrome (Dawood et al, 2009;Louie et al, 2009). The pdm H1N1 virus induced cytokine production and gene expression in dendritic cells and primary human macrophages at levels similar to or below those induced by seasonal viruses (Osterlund et al, 2010;Woo et al, 2010).…”

mentioning

confidence: 99%

Cytokine production by primary human macrophages infected with highly pathogenic H5N1 or pandemic H1N1 2009 influenza viruses

Sakabe

Iwatsuki‐Horimoto

Takano

et al. 2011

Journal of General Virology

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Highly pathogenic H5N1 avian influenza viruses have caused infection in humans, with a high mortality rate, since 1997. While the pathogenesis of this infection is not completely understood, hypercytokinaemia and alveolar macrophages are thought to play a role. To gain further insight into the cytokine-mediated pathogenesis of this infection in humans, we measured various cytokines produced by primary human macrophages infected with H5N1, pandemic H1N1 or seasonal influenza viruses. We found that many cytokines were produced at higher levels on infection with the H5N1 strains tested compared with seasonal influenza viruses. Interestingly, the extent of cytokine induction varied among the H5N1 strains and did not correlate with replicative ability in macrophages. Further, a pandemic H1N1 virus induced higher levels of several cytokines compared with seasonal viruses and some H5N1 strains. Our results demonstrate that high cytokine induction is not a universal feature of all H5N1 viruses.Highly pathogenic H5N1 avian influenza virus infection of humans has continued since 1997, with a mortality rate of nearly 60 % (Abdel-Ghafar et al., 2008; Claas et al., 1998). The mechanism underlying the pathogenesis of these infections is not fully understood, although hypercytokinaemia has been linked to the high pathogenicity (de Jong et al., 2005(de Jong et al., , 2006Peiris et al., 2004;To et al., 2001;Uiprasertkul et al., 2005). Alveolar macrophages are central players in both innate and adaptive immune responses to respiratory infection. In studies in vitro, human primary macrophages infected with H5N1 viruses produce higher levels of cytokines compared with those infected with seasonal viruses (Cheung et al., 2002;Guan et al., 2004;Lee et al., 2009;Mok et al., 2009;Woo et al., 2010). However, the H5N1 viruses examined in these studies were isolated before 2005, and the number of cytokines studied was limited.In 2009, a novel swine-origin H1N1 influenza virus (2009 pandemic H1N1 virus; pdm H1N1) caused a pandemic (Khan et al., 2009). During the first phase of this pandemic, 9 % of patients were hospitalized with pneumonia, respiratory failure or acute respiratory distress syndrome (Peng et al., 1999;Shimizu et al., 2007; Taylor et al., 2005). The phenotype of the human macrophages derived from the peripheral blood monocytes used in this study is similar to that of human alveolar macrophages (Shimizu et al., 2007; Taylor et al., 2005), suggesting that this is a useful model with which to study the dynamics of influenza virus infection in the human lung.To evaluate the susceptibility of primary human macrophages to avian H5N1 and human influenza viruses, we examined whether a-2,3-and a-2,6-linked sialic acids, which are avian and human virus receptors, respectively, were present on the cells by using lectins specific for these sialooligosaccharides: Sambucus nigra agglutinin (SNA) for a-2,6-linked and Maackia amurensis agglutinin II (MAAII) (Vector laboratories) for a-2,3-linked sialic acids. Cells were incubated with bi...

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“…The recent findings by Osterlund et al, demonstrating that influenza A/H1N109 is a relatively weak inducer of type I interferons, would indicate that this pyrogenic response is not due to the inclusion of the pandemic strain per se. 22 The retrospective nature and difficulty in using diagnostic coding data may have limited our ability to identify all cases requiring hospital presentation. Clinical data were collected from case notes limiting the volume of data collected.…”

Section: Discussionmentioning

confidence: 99%

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: Clinical features and potential mechanisms

Blyth

Currie

Wiertsema³

et al. 2011

Vaccine

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Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons

Cited by 147 publications

References 47 publications

Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I-like alveolar epithelial cells in vitro

Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I-like alveolar epithelial cells in vitro

Cytokine production by primary human macrophages infected with highly pathogenic H5N1 or pandemic H1N1 2009 influenza viruses

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: Clinical features and potential mechanisms

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