Dataset Information

Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice.

ABSTRACT:

Rationale

Infection with rhinovirus (RV) triggers exacerbations of asthma and chronic obstructive lung disease.

Objectives

We sought to develop a mouse model of RV employing RV1B, a minor group serotype that binds to the low-density lipoprotein receptor.

Methods

C57BL/6 mice were inoculated intranasally with RV1B, replication-deficient ultraviolet (UV)-irradiated RV1B, or RV39, a major group virus.

Measurements and main results

Viral RNA was present in the lungs of RV1B-treated mice, but not in those exposed to UV-irradiated RV1B or RV39. Lung homogenates of RV-treated mice contained infectious RV 4 days after inoculation. RV1B exposure induced neutrophilic and lymphocytic airway inflammation, as well as increased lung expression of KC, macrophage-inflammatory protein-2, and IFN-alpha and IFN-beta. RV1B-exposed mice showed airway hyperresponsiveness 1 and 4 days after inoculation. UV-irradiated RV1B induced modest neutrophilic airway inflammation and hyperresponsiveness 1 day after exposure. Both RV1B and UV-irradiated RV1B, but not RV39, increased lung phosphorylation of Akt. Confocal immunofluorescence showed colocalization of RV1B and phospho-Akt in the airway epithelium. Finally, pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 attenuated chemokine production and neutrophil infiltration.

Conclusions

We conclude that RV1B induces airway inflammation in vivo. Evidence is presented that viral replication occurs in vivo and is required for maximal responses. On the other hand, viral replication was not required for a subset of RV-induced responses, including neutrophilic inflammation, airway hyperresponsiveness, and Akt phosphorylation. Finally, phosphatidylinositol 3-kinase/Akt signaling is required for maximal RV1B-induced airway neutrophilic inflammation, likely via its essential role in virus internalization.

SUBMITTER: Newcomb DC

PROVIDER: S-EPMC2383993 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Publications

Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice.

Newcomb Dawn C DC Sajjan Umadevi S US Nagarkar Deepti R DR Wang Qiong Q Nanua Suparna S Zhou Ying Y McHenry Christina L CL Hennrick Kenneth T KT Tsai Wan C WC Bentley J Kelley JK Lukacs Nicholas W NW Johnston Sebastian L SL Hershenson Marc B MB

American journal of respiratory and critical care medicine 20080214 10

<h4>Rationale</h4>Infection with rhinovirus (RV) triggers exacerbations of asthma and chronic obstructive lung disease.<h4>Objectives</h4>We sought to develop a mouse model of RV employing RV1B, a minor group serotype that binds to the low-density lipoprotein receptor.<h4>Methods</h4>C57BL/6 mice were inoculated intranasally with RV1B, replication-deficient ultraviolet (UV)-irradiated RV1B, or RV39, a major group virus.<h4>Measurements and main results</h4>Viral RNA was present in the lungs of R ...[more]

PMID: 18276942

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Project description:Impaired interferon (IFN) production has been observed in various obstructive respiratory diseases. This contributes to enhanced sensitivity towards viral infections triggering acute exacerbations. To compensate for this impaired host IFN response, there is need to explore new therapeutic strategies, like exogenous administration of IFNs as prophylactic treatment. In the present study, we examined the protective potential of IFN-?1 and compared it with the previously established protecting effect of IFN-?. A549 cells and human primary bronchial epithelial cells were first treated with either IFN-? (500 IU/ml) or IFN-?1 (500 ng/ml) for 18 h. For infection, two approaches were adopted: i) Continuous scenario: after pre-treatment, cells were infected immediately for 24 h with human rhinovirus 1B (HRV1B) in IFN-containing medium, or were cultured for another 72 h in IFN-containing medium, and then infected for 24 h with HRV1B, ii) Pre-treatment scenario: IFN-containing medium was replaced after 18 h and cells were infected for 4 h either immediately after pre-treatment or after additional culturing for 72 h in IFN-free medium. The protective effect was evaluated in terms of reduction in the number of viral copies/infectious progeny, and enhanced expression of IFN-stimulated genes (ISGs). In both cell types and in both approaches, IFN-?1 and IFN-? treatment resulted in pronounced and long-lasting antiviral effects exemplified by significantly reduced viral copy numbers and diminished infectious progeny. This was associated with strong up-regulation of multiple ISGs. However, in contrast to the IFN-? induced expression of ISGs, which decreased over time, expression of ISGs induced by IFN-?1 was sustained or even increased over time. Here we demonstrate that the protective potential of IFN-?1 is comparable to IFN-?. Yet, the long-lasting induction of ISGs by IFN-?1 and most likely less incitement of side effects due to more localized expression of its receptors could make it an even more promising candidate for prophylactic treatment than IFN-?.

Project description:BackgroundThe nature of bronchial mucosal inflammation and its physiologic and clinical significance in rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal inflammatory response and its association with physiologic and clinical outcomes in an experimental model of rhinovirus-induced asthma exacerbations.MethodsWe used immunohistochemistry methods to detect phenotypes of inflammatory cells infiltrating the bronchial mucosa before and after experimental rhinovirus infection in 10 subjects with asthma and 15 normal subjects.ResultsCompared with baseline, rhinovirus infection significantly increased the number of epithelial (P = .005) and subepithelial (P = .017) neutrophils in subjects with asthma only and subepithelial CD68+ macrophages in both subjects with asthma (P = .009) and normal subjects (P = .018) but more so in those with asthma (P = .021). Numbers of CD45+, CD68+, and CD20+ cells; neutrophils; and eosinophils at day 4 postinfection were positively associated with virus load (r = 0.50-0.72, P = .016-0.03). At acute infection in subjects with asthma, CD4+ cells correlated with chest symptom scores (r = 0.69, P = .029), the fall in the 10% fall in FEV1 (PC10) correlated with neutrophils (r = -0.89, P = .029), the PC10 correlated inversely with CD4+ (r = -0.67, P = .023) and CD8+ cells (r = -0.65, P = .03), the 20% fall in FEV1 was inversely associated with CD20+ cells (r = -0.65, P = .03), and higher epithelial CD8+ cell counts were significantly associated with a greater maximum fall in FEV1 (r = -0.72, P = .03), whereas higher subepithelial mast cell counts were significantly associated with a lower maximum percent fall in peak expiratory flow (r = 0.8, P = .024).ConclusionsIn subjects with asthma, rhinovirus infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infiltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function.

Dataset Information

Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice.

Similar Datasets

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