Abstract
Replication, cell tropism and the magnitude of the host's antiviral immune response each contribute to the resulting pathogenicity of influenza A viruses (IAV) in humans. In contrast to seasonal IAV in human cases, the 2009 H1N1 pandemic IAV (H1N1pdm) shows a greater tropism for infection of the lung similar to H5N1. We hypothesized that host responses during infection of well-differentiated, primary human bronchial epithelial cells (wd-NHBE) may differ between seasonal (H1N1 A/BN/59/07) and H1N1pdm isolates from a fatal (A/KY/180/10) and nonfatal (A/KY/136/09) case. For each virus, the level of infectious virus and host response to infection (gene expression and apical/basal cytokine/chemokine profiles) were measured in wd-NHBE at 8, 24, 36, 48 and 72 hours post-infection (hpi). At 24 and 36 hpi, KY/180 showed a significant, ten-fold higher titer as compared to the other two isolates. Apical cytokine/chemokine levels of IL-6, IL-8 and GRO were similar in wd-NHBE cells infected by each of these viruses. At 24 and 36 hpi, NHBE cells had greater levels of pro-inflammatory cytokines including IFN-α, CCL2, TNF-α, and CCL5, when infected by pandemic viruses as compared with seasonal. Polarization of IL-6 in wd-NHBE cells was greatest at 36 hpi for all isolates. Differential polarized secretion was suggested for CCL5 across isolates. Despite differences in viral titer across isolates, no significant differences were observed in KY/180 and KY/136 gene expression intensity profiles. Microarray profiles of wd-NHBE cells diverged at 36 hpi with 1647 genes commonly shared by wd-NHBE cells infected by pandemic, but not seasonal isolates. Significant differences were observed in cytokine signaling, apoptosis, and cytoskeletal arrangement pathways. Our studies revealed differences in temporal dynamics and basal levels of cytokine/chemokine responses of wd-NHBE cells infected with each isolate; however, wd-NHBE cell gene intensity profiles were not significantly different between the two pandemic isolates suggesting post-transcriptional or later differences in viral-host interactions.
Highlights
The 2009 pandemic H1N1 influenza virus (H1N1pdm) arose through reassortment of two preexisting swine influenza viruses, a Eurasian avian-like virus and a North American triple reassortant virus [1,2]
Recent studies evaluating the pathogenesis of 2009 H1N1 pandemic IAV (H1N1pdm) in bronchial epithelial cells suggest that differentiation status of bronchial epithelial cells has a profound impact on the infection efficiency of different influenza strains and the host innate immune responses [9]
We sought to compare host responses in a wd-NHBE cell culture model to determine whether lung epithelial cells infection differed between seasonal and pandemic influenza isolates
Summary
The 2009 pandemic H1N1 influenza virus (H1N1pdm) arose through reassortment of two preexisting swine influenza viruses, a Eurasian avian-like virus and a North American triple reassortant virus [1,2]. Epidemiological data illustrated the speed of global spread of the 2009 pandemic virus; including significantly high infection attack rates in children and an 80% of H1N1pdm deaths in people younger than 65 years of age [3]. This was unlike seasonal influenza A virus (IAV) where morbidity and mortality are mainly seen in the elderly [4]. The illness associated with H1N1pdm infection was, very similar to seasonal influenza [5]. Immunohistopathology of patients with lethal disease confirmed positive for H1N1pdm identified the major cellular targets of infection as being upper respiratory epithelial cells, type II pneumocytes, and occasionally macrophages, which is similar to the pattern previously observed in H5N1 cases [8]
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