Differential Induction of Type I and Type III Interferons by Swine and Human Origin H1N1 Influenza A Viruses in Porcine Airway Epithelial Cells

Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized, protective IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis.

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Infection Studies in Pigs and Porcine Airway Epithelial Cells Reveal an Evolution of A(H1N1)pdm09 Influenza A Viruses Toward Lower Virulence

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy719 ◽

2019 ◽

Vol 219 (10) ◽

pp. 1596-1604 ◽

Cited By ~ 3

Author(s):

Yuguang Fu ◽

Ralf Dürrwald ◽

Fandan Meng ◽

Jie Tong ◽

Nai-Huei Wu ◽

...

Keyword(s):

Epithelial Cells ◽

Influenza A ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Influenza A Viruses

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Unique Transcriptional Architecture in Airway Epithelial Cells and Macrophages Shapes Distinct Responses following Influenza Virus Infection Ex Vivo

Journal of Virology ◽

10.1128/jvi.01986-18 ◽

2019 ◽

Vol 93 (6) ◽

Cited By ~ 6

Author(s):

Joel Z. Ma ◽

Wy Ching Ng ◽

Luke Zappia ◽

Linden J. Gearing ◽

Moshe Olshansky ◽

...

Keyword(s):

Steady State ◽

Epithelial Cells ◽

Rna Sequencing ◽

Influenza A Virus ◽

Influenza A ◽

Cell Types ◽

Airway Epithelial Cells ◽

Type I ◽

Airway Epithelial ◽

Transcriptional Responses

ABSTRACT Airway epithelial cells and macrophages differ markedly in their responses to influenza A virus (IAV) infection. To investigate transcriptional responses underlying these differences, purified subsets of type II airway epithelial cells (ATII) and alveolar macrophages (AM) recovered from the lungs of mock- or IAV-infected mice at 9 h postinfection were subjected to RNA sequencing. This time point was chosen to allow for characterization of cell types first infected with the virus inoculum, prior to multicycle virus replication and the infiltration of inflammatory cells into the airways. In the absence of infection, AM predominantly expressed genes related to immunity, whereas ATII expressed genes consistent with their physiological roles in the lung. Following IAV infection, AM almost exclusively activated cell-intrinsic antiviral pathways that were dependent on interferon (IFN) regulatory factor 3/7 (IRF3/7) and/or type I IFN signaling. In contrast, IAV-infected ATII activated a broader range of physiological responses, including cell-intrinsic antiviral pathways, which were both independent of and dependent on IRF3/7 and/or type I IFN. These data suggest that transcriptional profiles hardwired during development are a major determinant underlying the different responses of ATII and AM to IAV infection. IMPORTANCE Airway epithelial cells (AEC) and airway macrophages (AM) represent major targets of influenza A virus (IAV) infection in the lung, yet the two cell types respond very differently to IAV infection. We have used RNA sequencing to define the host transcriptional responses in each cell type under steady-state conditions as well as following IAV infection. To do this, different cell subsets isolated from the lungs of mock- and IAV-infected mice were subjected to RNA sequencing. Under steady-state conditions, AM and AEC express distinct transcriptional activities, consistent with distinct physiological roles in the airways. Not surprisingly, these cells also exhibited major differences in transcriptional responses following IAV infection. These studies shed light on how the different transcriptional architectures of airway cells from two different lineages drive transcriptional responses to IAV infection.

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Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells

Thorax ◽

10.1136/thoraxjnl-2011-200405 ◽

2012 ◽

Vol 67 (6) ◽

pp. 517-525 ◽

Cited By ~ 25

Author(s):

Marjolaine Vareille ◽

Elisabeth Kieninger ◽

Marco P Alves ◽

Brigitte S Kopf ◽

Alexander Möller ◽

...

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Airway Epithelial Cells ◽

Type I ◽

Airway Epithelial ◽

Type Iii ◽

Interferon Induction ◽

Cystic Fibrosis Airway ◽

Type Iii Interferon

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Eosinophil Responses at the Airway Epithelial Barrier during the Early Phase of Influenza a Virus Infection in C57BL/6 Mice

Cells ◽

10.3390/cells10030509 ◽

2021 ◽

Vol 10 (3) ◽

pp. 509 ◽

Cited By ~ 1

Author(s):

Meenakshi Tiwary ◽

Robert J. Rooney ◽

Swantje Liedmann ◽

Kim S. LeMessurier ◽

Amali E. Samarasinghe

Keyword(s):

Epithelial Cells ◽

Influenza A Virus ◽

Early Phase ◽

Influenza A ◽

Airway Epithelial Cells ◽

Epithelial Barrier ◽

Virus Infectivity ◽

Airway Epithelial ◽

In Vivo Models

Eosinophils, previously considered terminally differentiated effector cells, have multifaceted functions in tissues. We previously found that allergic mice with eosinophil-rich inflammation were protected from severe influenza and discovered specialized antiviral effector functions for eosinophils including promoting cellular immunity during influenza. In this study, we hypothesized that eosinophil responses during the early phase of influenza contribute to host protection. Using in vitro and in vivo models, we found that eosinophils were rapidly and dynamically regulated upon influenza A virus (IAV) exposure to gain migratory capabilities to traffic to lymphoid organs after pulmonary infection. Eosinophils were capable of neutralizing virus upon contact and combinations of eosinophil granule proteins reduced virus infectivity through hemagglutinin inactivation. Bi-directional crosstalk between IAV-exposed epithelial cells and eosinophils occurred after IAV infection and cross-regulation promoted barrier responses to improve antiviral defenses in airway epithelial cells. Direct interactions between eosinophils and airway epithelial cells after IAV infection prevented virus-induced cytopathology in airway epithelial cells in vitro, and eosinophil recipient IAV-infected mice also maintained normal airway epithelial cell morphology. Our data suggest that eosinophils are important in the early phase of IAV infection providing immediate protection to the epithelial barrier until adaptive immune responses are deployed during influenza.

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Comparison Of Host Responses Elicited By Avian H5N1, 2009 Pandemic H1N1, And Seasonal H1N1 Influenza Viruses In Human Airway Epithelial Cells

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6022 ◽

2011 ◽

Author(s):

Anand C. Patel ◽

Noah Yoo ◽

Subhajit Poddar ◽

Nadezhda E. Yun ◽

Yong Zhang ◽

...

Keyword(s):

Epithelial Cells ◽

H1n1 Influenza ◽

Airway Epithelial Cells ◽

Influenza Viruses ◽

Host Responses ◽

Pandemic H1n1 ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

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FOXO3a regulates rhinovirus-induced innate immune responses in airway epithelial cells

Scientific Reports ◽

10.1038/s41598-019-54567-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Joao Gimenes-Junior ◽

Nicole Owuar ◽

Hymavathi Reddy Vari ◽

Wuyan Li ◽

Nathaniel Xander ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Lung Inflammation ◽

Inflammatory Cytokine ◽

Airway Epithelial Cell ◽

Critical Role ◽

Airway Epithelial Cells ◽

Type I ◽

Airway Epithelial ◽

Antiviral Responses

AbstractForkhead transcription factor class O (FOXO)3a, which plays a critical role in a wide variety of cellular processes, was also found to regulate cell-type-specific antiviral responses. Airway epithelial cells express FOXO3a and play an important role in clearing rhinovirus (RV) by mounting antiviral type I and type III interferon (IFN) responses. To elucidate the role of FOXO3a in regulating antiviral responses, we generated airway epithelial cell-specific Foxo3a knockout (Scga1b1-Foxo3a−/−) mice and a stable FOXO3a knockout human airway epithelial cell line. Compared to wild-type, Scga1b1-Foxo3a−/− mice show reduced IFN-α, IFN-β, IFN-λ2/3 in response to challenge with RV or double-stranded (ds)RNA mimic, Poly Inosinic-polycytidylic acid (Poly I:C) indicating defective dsRNA receptor signaling. RV-infected Scga1b1-Foxo3a−/− mice also show viral persistence, enhanced lung inflammation and elevated pro-inflammatory cytokine levels. FOXO3a K/O airway epithelial cells show attenuated IFN responses to RV infection and this was associated with conformational change in mitochondrial antiviral signaling protein (MAVS) but not with a reduction in the expression of dsRNA receptors under unstimulated conditions. Pretreatment with MitoTEMPO, a mitochondrial-specific antioxidant corrects MAVS conformation and restores antiviral IFN responses to subsequent RV infection in FOXO3a K/O cells. Inhibition of oxidative stress also reduces pro-inflammatory cytokine responses to RV in FOXO3a K/O cells. Together, our results indicate that FOXO3a plays a critical role in regulating antiviral responses as well as limiting pro-inflammatory cytokine expression. Based on these results, we conclude that FOXO3a contributes to optimal viral clearance and prevents excessive lung inflammation following RV infection.

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