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Abstract Background Pandemic 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. Methods We 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. Results Overall, 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. Conclusions Both 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.

Type I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β. Here we show that expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. In support of this NS1-mediated inhibition, we observed a reduction in expression of ifnar1 in ex vivo human non-tumor lung tissues infected with H5N1 and H1N1 viruses. Moreover, H1N1 and H5N1 virus infection of human monocyte-derived macrophages led to inhibition of both ifnar1 and ifnar2 expression. In addition, NS1 expression induces up-regulation of the JAK/STAT inhibitors, SOCS1 and SOCS3. By contrast, treatment of ex vivo human lung tissues with IFN-a results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections. [ABSTRACT FROM AUTHOR]

Human disease caused by highly pathogenic avian influenza (H5N1) is associated with fulminant viral pneumonia and mortality rates in excess of 60%. Cytokine dysregulation is thought to contribute to its pathogenesis. In comparison with human seasonal influenza (H1N1) viruses, clade 1, 2.1, and 2.2 H5N1 viruses induced higher levels of tumor necrosis factor-a in primary human macrophages. To understand viral genetic determinants responsible for this hyperinduction of cytokines, we constructed recombinant viruses containing different combinations of genes from high-cytokine (A/Vietnam/1203/04) and low-cytokine (A/WSN/33) phenotype H1N1 viruses and tested their cytokine-inducing phenotype in human macrophages. Our results suggest that the H5N1 polymerase gene segments, and to a lesser extent the NS gene segment, contribute to cytokine hyperinduction in human macrophages and that a putative H5 pandemic virus that may arise through genetic reassortment between H5N1 and one of the current seasonal influenza viruses may have a markedly altered cytokine phenotype. [ABSTRACT FROM AUTHOR]

Macrophages, a critical subset of innate immune cells, play a pivotal role in cytokine production during disease progression, tissue injury, and pathogen invasion. Their intricate involvement in the manifestation of chronic low-grade inflammation associated with the aging process is widely acknowledged. Notably, in aged tissues, macrophages exhibit an altered phenotype characterized by an augmented synthesis of pro-inflammatory cytokines and chemokines, a profile intimately associated with a phenomenon known as inflammaging. Macrophages possess the capacity to undergo cellular senescence, a state of permanent growth arrest, in response to diverse stressors, including aging. Senescent macrophages secrete an array of pro-inflammatory molecules, growth factors, and matrix metalloproteinases, collectively referred to as the Senescence-Associated Secretory Phenotype (SASP). The SASP exacerbates the state of chronic inflammation observed in aging tissues. Thus, disruptions in macrophage function and signaling pathways due to aging result in escalated production of inflammatory mediators, perpetuating inflammaging. Recent research has uncovered novel mechanisms centred around innate immune signaling and mitochondrial dysfunction in macrophages, highlighting their crucial role in the development of inflammaging and associated pathological conditions. This review delves into the latest scientific findings on these emerging mechanisms in macrophage senescence related to aging and explores the prospects of targeting macrophages to address age- associated conditions effectively.