<scp>TLR</scp>3 and <scp>MDA</scp>5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection.

Parsons, Kristy; Hsu, Alan; Wark, Peter

doi:10.1111/cea.12218

Cited by 70 publications

(65 citation statements)

References 29 publications

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“…Eosinophilic asthmatics also expressed lower levels of innate IFNs in addition to TLR7, a difference that was not observed for expression of TLR3, retinoic acid-inducible gene I or melanoma differentiation-associated gene 5. 27 These results are congruent with a recent study that mapped TLR7 expression in the airways of severe asthmatics. 28 Our results suggest a reciprocal regulation between IL-5-induced eosinophilia and TLR7 expression that affects antiviral IFN responses to RV (summary illustrated in figure 5).…”

Section: Discussionsupporting

confidence: 91%

“…This finding was of clinical relevance because we observed reduced TLR7 expression in endobronchial biopsies from asthmatic patients with eosinophilic inflammatory profiles. Eosinophilic asthmatics also expressed lower levels of innate IFNs in addition to TLR7, a difference that was not observed for expression of TLR3, retinoic acid-inducible gene I or melanoma differentiation-associated gene 5 27. These results are congruent with a recent study that mapped TLR7 expression in the airways of severe asthmatics 28…”

Section: Discussionsupporting

confidence: 87%

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Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia

Hatchwell

Collison

Girkin

et al. 2015

Thorax

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BackgroundAsthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood.ObjectivesTo investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection.MethodsWild-type and TLR7-deficient (Tlr7−/−) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC).ResultsAllergic Tlr7−/− mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFNγ release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFNλ2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils.ConclusionsThis implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 87%

Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia

Hatchwell

Collison

Girkin

et al. 2015

Thorax

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“…Activation of TLR3 then leads to the induction of other subsequent pattern recognition receptors such as retinoic acid inducible protein I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) (Wang et al, 2009). However, the exact subsequent inflammatory effects of TLR3-pathways stimulated by HRV are not well understood, and inflammation may result from an abnormal downstream signaling defect (Parsons et al, 2014). There have also been alternative sensing mechanisms proposed such as TLR7 and TLR8, though the data remain inconclusive as to their exact role in initiating an immune response to HRV (Morris et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Volatile emanations fromin vitroairway cells infected with human rhinovirus

et al. 2014

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Respiratory viral infections such as human rhinovirus (HRV) can lead to substantial morbidity and mortality, especially in people with underlying lung diseases such as asthma and COPD. One proposed strategy to detect viral infections non-invasively is by volatile organic compound (VOC) assessment via analysis of exhaled breath. The epithelial cells are one of the most important cell lines affected during respiratory infections as they are the first line of pathogen defense. Efforts to discover infection-specific biomarkers can be significantly aided by understanding the VOC emanations of respiratory epithelial cells. Here we test the hypothesis that VOCs obtained from the headspace of respiratory cell culture will differentiate healthy cells from those infected with HRV. Primary human tracheobronchial cells were cultured and placed in a system designed to trap headspace VOCs. HRV-infected cells were compared to uninfected control cells. In addition, cells treated with heat-killed HRV and poly(I:C), a TLR3 agonist, were compared to controls. The headspace was sampled with solid-phase microextraction fibers and VOCs were analyzed by gas chromatography/mass spectrometry. We determined differential expression of compounds such as aliphatic alcohols, branched hydrocarbons, and dimethyl sulfide by the infected cells, VOCs previously associated with oxidative stress and bacterial infection. We saw no major differences between the killed-HRV, poly(I:C), and control cell VOCs. We postulate that these compounds may serve as biomarkers of HRV infection, and that the production of VOCs is not due to TLR3 stimulation but does require active viral replication. Our novel approach may be used for the in vitro study of other important respiratory viruses, and ultimately it may aid in identifying VOC biomarkers of viral infection for point-of-care diagnostics.

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“…In vitro, there is considerable evidence of decreased production of interferon (IFN)-α2, IFN-β1 and IFN-λ2/3 by airway epithelial cells (AEC) from asthmatics, in response to stimulation with double-stranded RNA (dsRNA) or with RV [7-11]. This has been related to impaired toll-like receptor (TLR) and helicase signalling [12]. It has also been suggested that similar impairment is demonstrable in atopic individuals even without asthma [13], although this has not been confirmed.…”

Section: Introductionmentioning

confidence: 99%

Response of airway epithelial cells to double-stranded RNA in an allergic environment

et al. 2014

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BackgroundRespiratory viral infections are the most common trigger of acute exacerbations in patients with allergic asthma. The anti-viral response of airway epithelial cells (AEC) may be impaired in asthmatics, while cytokines produced by AEC may drive the inflammatory response. We investigated whether AEC cultured in the presence of Th2 cytokines associated with an allergic environment exhibited altered responses to double-stranded RNA, a virus-like stimulus.MethodsWe undertook preliminary studies using the MLE-12 cell line derived from mouse distal respiratory epithelial cells, then confirmed and extended our findings using low-passage human AEC. Cells were cultured in the absence or presence of the Th2 cytokines IL-4 and IL-13 for 48 hours, then stimulated with poly I:C for 4 hours. Expression of relevant anti-viral response and cytokine genes was assessed by quantitative real-time PCR. Secretion of cytokine proteins was assessed by immunoassay.ResultsFollowing stimulation with poly I:C, MLE-12 cells pre-treated with Th2 cytokines exhibited significantly higher levels of expression of mRNA for the cytokine genes Cxcl10 and Cxcl11, as well as a trend towards increased expression of Cxcl9 and Il6. Expression of anti-viral response genes was mostly unchanged, although Stat1, Ifit1 and Ifitm3 were significantly increased in Th2 cytokine pre-treated cells. Human AEC pre-treated with IL-4 and IL-13, then stimulated with poly I:C, similarly exhibited significantly higher expression of IL8, CXCL9, CXCL10, CXCL11 and CCL5 genes. In parallel, there was significantly increased secretion of CXCL8 and CCL5, as well as a trend towards increased secretion of CXCL10 and IL-6. Again, expression of anti-viral response genes was not decreased. Rather, there was significantly enhanced expression of mRNA for type III interferons, RNA helicases and other interferon-stimulated genes.ConclusionThe Th2 cytokine environment appears to promote increased production of pro-inflammatory chemokines by AEC in response to double-stranded RNA, which could help explain the exaggerated inflammatory response to respiratory viral infection in allergic asthmatics. However, any impairment of anti-viral host defences in asthmatics appears unlikely to be a consequence of Th2 cytokine-induced downregulation of the expression of viral response genes by AEC.

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TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection.

Abstract: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection.

Cited by 70 publications

References 29 publications

Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia

Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia

Volatile emanations fromin vitroairway cells infected with human rhinovirus

Response of airway epithelial cells to double-stranded RNA in an allergic environment

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