Detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization.

Bardin, Philip G.; Johnston, Sebastian L.; Sanderson, G.; Robinson, B.S.; Pickett, Mark A.; Fraenkel, David; Holgate, Stephen T.

doi:10.1165/ajrcmb.10.2.8110476

Cited by 84 publications

(59 citation statements)

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“…Although epithelial cells are the main target for HRV infection, several studies have indicated that HRV may be detected in the subepithelial layer by in situ hybridization (8,9) and that human lung fibroblasts are susceptible to HRV infection (10). Bronchial fibroblasts are part of the mesenchymal layer in the airway tissue and have the versatility to differentiate into other connective tissue families such as smooth muscle cells and myofibroblasts (11).…”

Section: H Uman Rhinoviruses (Hrv)mentioning

confidence: 99%

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Bedke

Haitchi

Xatzipsalti

et al. 2009

The Journal of Immunology

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Human rhinoviruses (HRV) are a major cause of asthma exacerbations and hospitalization. Studies using primary cultures suggest that this may be due to impaired production of type I and type III IFNs by asthmatic bronchial epithelial cells. Although epithelial cells are the main target for HRV infection, HRV can be detected in the subepithelial layer of bronchial mucosa from infected subjects by in situ hybridization. Therefore, we postulated that submucosal fibroblasts are also involved in the innate antiviral response to HRV infection in asthma. We found that regardless of subject group, bronchial fibroblasts were highly susceptible to RV1b infection. IL-8 and IL-6 were rapidly induced by either HRV or UV-irradiated virus, suggesting that these responses did not require viral replication. In contrast, RANTES expression was dependent on viral replication. Regardless of disease status, fibroblasts did not respond to HRV infection with significant induction of IFN-␤, even though both groups responded to synthetic dsRNA with similar levels of IFN-␤ expression. Exogenous IFN-␤ was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-␤ expression. Their susceptibility to infection may cause them to be a reservoir for HRV replication in the lower airways, especially in asthmatic subjects where there is reduced protection offered by epithelialderived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations.

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Section: H Uman Rhinoviruses (Hrv)mentioning

confidence: 99%

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Bedke

Haitchi

Xatzipsalti

et al. 2009

The Journal of Immunology

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“…The airway epithelial cell is the dominant site of HRV infection in vivo (5,6), and both upper and lower airway epithelial cells are infected at a similar frequency (7). HRV infections do not lead to overt changes in epithelial cell integrity or viability, but they can induce epithelial production of a number of chemokines and cytokines (8 -11).…”

mentioning

confidence: 99%

Selective Transcriptional Down-Regulation of Human Rhinovirus-Induced Production of CXCL10 from Airway Epithelial Cells via the MEK1 Pathway

Zaheer

Koetzler

Holden

et al. 2009

The Journal of Immunology

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Human rhinovirus (HRV) infections can trigger exacerbations of lower airway diseases. Infection of airway epithelial cells induces production of a number of proinflammatory chemokines that may exacerbate airway inflammation, including CXCL10, a chemoattractant for type 1 lymphocytes and NK cells. Primary human bronchial epithelial cells and the BEAS-2B human bronchial epithelial cell line were used to examine the role of MAPK pathways in HRV-16-induced production of CXCL10. Surprisingly, PD98059 and U0126, two inhibitors of the MEK1/2-ERK MAPK pathway, significantly enhanced HRV-16-induced CXCL10 mRNA and protein. This enhancement was not seen with IFN-β-induced production of CXCL10. Studies using small interfering RNA revealed that knockdown of MEK1, but not MEK2, was associated with enhanced HRV-induced CXCL10 production. Promoter construct studies revealed that PD98059 and U0126 enhanced HRV-16-induced transcriptional activation of CXCL10. HRV-16-induced promoter activation was regulated by two NF-κB binding sites, κB1 and κB2, and by an IFN-stimulated response element. Inhibitors of the MEK1/2-ERK pathway did not alter HRV-16-induced activation of tandem repeat κB1 or κB2 constructs, nor did they alter HRV-16-induced nuclear translocation/binding of NF-κB to either κB1 or κB2 recognition sequences. Furthermore, PD98059 and U0126 did not alter phosphorylation or degradation of IκBα. In contrast, inhibitors of the MEK1/2-ERK pathway, and small interfering RNA knockdown of MEK1, enhanced nuclear translocation/binding of IFN regulatory factor (IRF)-1 to the IFN-stimulated response element recognition sequence in HRV-16 infected cells. We conclude that activation of MEK1 selectively down-regulates HRV-16-induced expression of CXCL10 via modulation of IRF-1 interactions with the gene promoter in human airway epithelial cells.

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“…Moreover, it has been shown that virus also spreads to the lower airway epithelium (3,35). In contrast to some other viruses, HRV does not induce overt epithelial cytotoxicity.…”

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confidence: 99%

Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

Wiehler

Proud²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Human rhinovirus (HRV) infections are associated with exacerbations of asthma and chronic obstructive pulmonary disease that are characterized by a selective neutrophil infiltration. IL-17A, a cytokine derived primarily from activated T cells, has been linked to neutrophilic inflammation of the airways. We hypothesized that IL-17A alters the response of HRV-infected epithelial cells to modulate airway inflammatory cell populations. IL-17A synergistically enhanced HRV-16-induced epithelial production of the neutrophil chemoattractant, IL-8, as well as human β-defensin-2 (HBD-2), a chemoattractant for immature dendritic cells and memory T cells, but suppressed viral production of the eosinophil chemoattractant, RANTES. These effects were not due to alterations of viral uptake or replication by IL-17A. The synergy between HRV-16 and IL-17A for IL-8 protein production was both dose- and time-dependent. IL-8 induction by IL-17A or HRV-16, alone and in combination, was reduced by inhibitors of the p38 and p44/42 MAPK pathways. By contrast, induction of HBD-2 depended on the activation of the p38 and JNK pathways. The ability of IL-17A to synergistically enhance HRV-induced IL-8 is mediated posttranscriptionally, since IL-8 promoter activation by the combination of the two stimuli was merely additive, whereas the combination of IL-17A and HRV-16 led to stabilization of IL-8 mRNA. Similarly, stimulation of HBD-2 promoter constructs by the combination of IL-17A and HRV-16 was no more than the sum of the individual responses. Further studies are needed to examine HBD-2 mRNA stability. Taken together, these data represent the first demonstration that IL-17A can modify epithelial responses to HRV in a manner that would be expected to favor the recruitment of neutrophils, immature dendritic cells, and memory T cells to the airways.

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Detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization.

Cited by 84 publications

References 0 publications

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Contribution of Bronchial Fibroblasts to the Antiviral Response in Asthma

Selective Transcriptional Down-Regulation of Human Rhinovirus-Induced Production of CXCL10 from Airway Epithelial Cells via the MEK1 Pathway

Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

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