Bartlett, N.W. et al. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat. Med. 14, 199-204

Department of Respiratory Medicine, UK National Heart and Lung Institute, and Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London W2 1PG, UK.
Nature medicine (Impact Factor: 27.36). 03/2008; 14(2):199-204. DOI: 10.1038/nm1713
Source: PubMed


Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.

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    • "Indeed, rhinovirus infection induces the production of cytokines and chemokines including interleukin-6 (IL-6), interleukin-8 (IL-8), regulated on activation normal T cell expressed and secreted (RANTES), interleukin-10 (IL-10) and interferon-b in vivo and in vitro (Bartlett et al., 2008; Message et al., 2008; Subauste et al., 1995; Zhu et al., 1996). The production of most cytokines and chemokines is HRV replication dependent (Bartlett et al., 2008), has pro-inflammatory effects and correlates with the severity of cold symptoms (Gern et al., 2002). Moreover, rhinovirus infection of both primary bronchial epithelial cells and a respiratory epithelial cell line markedly increases cell surface expression of intercellular adhesion molecule-1 (ICAM-1) (Papi and Johnston, 1999) the cellular receptor for the major group (90%) of rhinoviruses (Greve et al., 1989; Uncapher et al., 1991). "
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    ABSTRACT: Human rhinoviruses (HRV), the cause of common colds, are the most frequent precipitants of acute exacerbation of asthma and chronic obstructive pulmonary disease, as well as causes of other serious respiratory diseases. No vaccine or antiviral agents are available for the prevention or treatment of HRV infection. Resveratrol exerts antiviral effect against different DNA and RNA viruses. The antiviral effect of a new resveratrol formulation containing carboxymethylated glucan was analyzed in H1HeLa cell monolayers and ex vivo nasal epithelia infected with HRV-16. Virus yield was evaluated by plaque assay and expression of viral capsid proteins by Western blot. IL-10, IFN-β, IL-6, IL-8 and RANTES levels were evaluated by ELISA assay. ICAM-1 was assessed by Western blot and immunofluorescence. Resveratrol exerted a high, dose-dependent, antiviral activity against HRV-16 replication and reduced virus-induced secretion of IL-6, IL-8 and RANTES to levels similar to that of uninfected nasal epithelia. Basal levels of IL-6 and RANTES were also significantly reduced in uninfected epithelia confirming an anti-inflammatory effect of the compound. HRV-induced expression of ICAM-1 was reversed by resveratrol. Resveratrol may be useful for a therapeutic approach to reduce HRV replication and virus-induced cytokine/chemokine production. Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 08/2015; 123. DOI:10.1016/j.antiviral.2015.08.010 · 3.94 Impact Factor
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    • "SPLUNC1 KO and control mice (8–12 weeks old) were anesthetized by intra-peritoneal (i.p.) injection of ketamine (80 mg/kg) and xylazine (10 mg/kg), and intranasally inoculated with HRV-1B at 5×106 pfu/mouse as HRV-1B is the only HRV that can directly infect mouse lungs [32]. After 24 h, the left lung was homogenized for examining HRV RNA levels by quantitative real-time RT-PCR. "
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    ABSTRACT: Background/Objective The use of electronic cigarettes (e-cigarettes) is rapidly increasing in the United States, especially among young people since e-cigarettes have been perceived as a safer alternative to conventional tobacco cigarettes. However, the scientific evidence regarding the human health effects of e-cigarettes on the lung is extremely limited. The major goal of our current study is to determine if e-cigarette use alters human young subject airway epithelial functions such as inflammatory response and innate immune defense against respiratory viral (i.e., human rhinovirus, HRV) infection. Methodology/Main Results We examined the effects of e-cigarette liquid (e-liquid) on pro-inflammatory cytokine (e.g., IL-6) production, HRV infection and host defense molecules (e.g., short palate, lung, and nasal epithelium clone 1, SPLUNC1) in primary human airway epithelial cells from young healthy non-smokers. Additionally, we examined the role of SPLUNC1 in lung defense against HRV infection using a SPLUNC1 knockout mouse model. We found that nicotine-free e-liquid promoted IL-6 production and HRV infection. Addition of nicotine into e-liquid further amplified the effects of nicotine-free e-liquid. Moreover, SPLUNC1 deficiency in mice significantly increased lung HRV loads. E-liquid inhibited SPLUNC1 expression in primary human airway epithelial cells. These findings strongly suggest the deleterious health effects of e-cigarettes in the airways of young people. Our data will guide future studies to evaluate the impact of e-cigarettes on lung health in human populations, and help inform the public about potential health risks of e-cigarettes.
    PLoS ONE 09/2014; 9(9):e108342. DOI:10.1371/journal.pone.0108342 · 3.23 Impact Factor
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    • "Another potential concern relates to our model’s dependence on minor group viruses. However, effects of RV1B infection on wild-type mice are indistinguishable from those of RV16, a major group virus, on transgenic human ICAM-1 mice [63]. Major and minor group viruses induce nearly identical patterns of gene expression in cultured airway epithelial cells [64]. "
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    ABSTRACT: Background The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease. Methods Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate. Results In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-α. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-α, IFN-γ and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-α and IL-17A production by F4/80+, CD11b+ macrophages. Conclusions OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection.
    Respiratory Research 06/2014; 15(1):63. DOI:10.1186/1465-9921-15-63 · 3.09 Impact Factor
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