The 2009 Pandemic H1N1 and Triple-Reassortant Swine H1N1 Influenza Viruses Replicate Efficiently but Elicit an Attenuated Inflammatory Response in Polarized Human Bronchial Epithelial Cells

Zeng, Hui; Pappas, Claudia; Katz, Jacqueline M.; Tumpey, Terrence M.

doi:10.1128/jvi.01568-10

Cited by 47 publications

(50 citation statements)

References 45 publications

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“…Leukocyte chemoattractant chemokines, such as CXCL8, CCL2, and TNF-␣, are known to be present at sites of infection following experimental human IAV infection (47), and levels are higher in patients with the H1N1pdm virus than in those with seasonal IAV (48,75). Previously, we and others have shown increased secretion of leukocyte chemoattractant chemokines (TNF-␣, CCL2, CCL3, and CXCL8) following in vitro infection of a welldifferentiated normal human bronchial epithelial cell culture with the H1N1pdm virus relative to that with seasonal IAV infection (58,76). In IAV-infected ferrets, we and others have shown increased expression of other leukocyte chemoattractant genes (CCL2, CCL3, and CXCL10), as well as leukocyte-specific genes (G-CSFR, M-CSFR, CD11b, and cathepsin B [CTSB]), in the blood (77)(78)(79).…”

Section: Discussionmentioning

confidence: 99%

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Camp

Bağcı

Chu

et al. 2015

J Virol

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Infection of the lower respiratory tract by influenza A viruses results in increases in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. Here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 H1N1 pandemic influenza A virus (H1N1pdm virus). Neutrophil levels rose in the lungs of H1N1pdm virus-infected ferrets 6 h postinfection and became concentrated at areas of the H1N1pdm virusinfected bronchiolar epithelium by 1 day postinfection (dpi). In addition, neutrophil levels were increased throughout the alveolar spaces during the first 3 dpi and returned to baseline by 6 dpi. Histochemical staining revealed that neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3 levels, but not CXCL8/interleukin 8 (IL-8) levels, were higher within discrete lung microenvironments and coincided with increased infiltration of neutrophils into the lung. We used live imaging of ferrets to monitor host responses within the lung over time with [18 F]fluorodeoxyglucose (FDG). Sites in the H1N1pdm virus-infected ferret lung with high FDG uptake had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm virus-infected ferret lung globally and focally at sites of infection. Increased neutrophil levels in microenvironments did not correlate with increased FDG uptake; hence, FDG uptake may reflect prior infection and inflammation of lungs that have experienced damage, as evidenced by bronchial regeneration of tissues in the lungs at sites with high FDG levels. IMPORTANCESevere influenza disease is characterized by an acute infection of the lower airways that may progress rapidly to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ, and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm virus infection, we used live imaging and comprehensive histological analyses to address specific hypotheses regarding spatial and temporal relationships that occur during the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung) but also a distinct pattern of localized accumulation within the microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.T he annual impact of seasonal influenza A viruses (IAV) on public health is fairly predictable and is mostly preventable in normal, healthy populations with currently...

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Section: Discussionmentioning

confidence: 99%

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Camp

Bağcı

Chu

et al. 2015

J Virol

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“…Human airway epithelial Calu-3 cells, obtained from the ATCC, were cultured on 12-well plate transwells as described previously (19). Briefly, polarized Calu-3 cells grown on transwells were inoculated apically in triplicate with HPAI H5 or seasonal H1N1 viruses at a multiplicity of infection (MOI) of 0.01 for 1 h, washed, and then incubated at 33°C or 37°C in a 5% CO 2 atmosphere.…”

Section: Viruses Virus Stocks Of Hpaimentioning

confidence: 99%

Pathogenesis and Transmission of Novel Highly Pathogenic Avian Influenza H5N2 and H5N8 Viruses in Ferrets and Mice

Pulit-Penaloza

Sun

Creager

et al. 2015

J Virol

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A novel highly pathogenic avian influenza (HPAI) H5N8 virus, first detected in January 2014 in poultry and wild birds in South Korea, has spread throughout Asia and Europe and caused outbreaks in Canada and the United States by the end of the year. The spread of H5N8 and the novel reassortant viruses, H5N2 and H5N1 (H5Nx), in domestic poultry across multiple states in the United States pose a potential public health risk. To evaluate the potential of cross-species infection, we determined the pathogenicity and transmissibility of two Asian-origin H5Nx viruses in mammalian animal models. The newly isolated H5N2 and H5N8 viruses were able to cause severe disease in mice only at high doses. Both viruses replicated efficiently in the upper and lower respiratory tracts of ferrets; however, the clinical symptoms were generally mild, and there was no evidence of systemic dissemination of virus to multiple organs. Moreover, these influenza H5Nx viruses lacked the ability to transmit between ferrets in a direct contact setting. We further assessed viral replication kinetics of the novel H5Nx viruses in a human bronchial epithelium cell line, Calu-3. Both H5Nx viruses replicated to a level comparable to a human seasonal H1N1 virus, but significantly lower than a virulent Asian-lineage H5N1 HPAI virus. Although the recently isolated H5N2 and H5N8 viruses displayed moderate pathogenicity in mammalian models, their ability to rapidly spread among avian species, reassort, and generate novel strains underscores the need for continued risk assessment in mammals. O n 16 December 2014, the U.S. Department of Agriculture (USDA) confirmed the presence of a novel highly pathogenic avian influenza (HPAI) H5N8 virus in a captive gyrfalcon and H5N2 virus in a northern pintail duck from Whatcom County, Washington (1). This represented the first appearance of HPAI H5 virus in the United States since 2004 when H5N2 subtype virus was confirmed on a poultry farm in Texas (2). HPAI H5N8 viruses were first reported in duck farms in eastern China in 2010, and in early 2014 a novel reassortant H5N8 virus was detected in poultry in South Korea (3-5). The novel virus, belonging to Eurasian lineage clade 2.3.4.4 (formerly clade 2.3.4.6), subsequently spread to China, Japan, and five countries in Europe (6, 7). In November 2014, the virus was detected on chicken and turkey farms in British Columbia, Canada, followed by Washington State, USA, the following month (8). The novel H5N8 viruses continue to spread to multiple regions and have been found in three North America flyways (Pacific, Central, and Mississippi), where wild-bird migrations occur (USDA, Animal and Plant Health Inspection Service [http://www.aphis.usda.gov]). In addition, genetic reassortment with circulating North American avian influenza viruses has resulted in novel HPAI viruses, including H5N2 and H5N1 subtypes. These novel reassortant viruses carry a Eurasian-origin hemagglutinin (HA) gene genetically related to H5N8 viruses detected in South Korea in 2014 and the neura...

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“…Using in vitro models that closely mimic physiological conditions within the lungs in evaluating respiratory infections is an important approach in elucidation of potential differences between strains with different virulence [321,322] H1N1pdm being more efficient [90]. Furthermore, a study comparing different H1N1pdm isolates in udNHBE cells show critical differences in levels of cytokines and chemokines elicited from cells infected with closely-related influenza isolates [91].…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the spatial distribution and concentration of potential receptors associated within different areas of the respiratory tract and/or different cell types are integral in the study of IAV infection and disease [75,[88][89][90][91].…”

Section: Influenza a Virus Life Cycyle Attachment And Bindingmentioning

confidence: 99%

“…Seasonal IAV and H1N1pdm viruses enter and replicate efficiently into non-ciliated cells which are present in the epithelial cell layer in both the large and small airways of the lower respiratory tract, while H5N1 enters and replicates more efficiently in ciliated cells within the small airways [74,75,[83][84][85][86]. Hence, the spatial distribution and concentration of potential receptors associated within different areas of the respiratory tract and/or different cell types are integral in the study of IAV infection and disease [75,[88][89][90][91]. Further, while the lung epithelium is a primary target for infection [46], it is a highly complex environment composed of a heterogeneous cell population, including secretory (Clara), goblet (secretory/mucus), ciliated, and basal cells that differ in frequency and distribution depending on location in the lung [317].…”

Section: Human Immune Cell Culture Models To Study Iavmentioning

confidence: 99%

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Early host response and immune signaling to 2009 pandemic influenza A (H1N1) viruses in primary cell culture models.

Gerlach¹

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The 2009 Pandemic H1N1 and Triple-Reassortant Swine H1N1 Influenza Viruses Replicate Efficiently but Elicit an Attenuated Inflammatory Response in Polarized Human Bronchial Epithelial Cells

Cited by 47 publications

References 45 publications

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils

Pathogenesis and Transmission of Novel Highly Pathogenic Avian Influenza H5N2 and H5N8 Viruses in Ferrets and Mice

Early host response and immune signaling to 2009 pandemic influenza A (H1N1) viruses in primary cell culture models.

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