| Autor: |
Paul S. Foster, Peter A. B. Wark, J. Li, Sebastian L. Johnston, Adam Collison, Simon Phipps, Pereira A. De Siqueira, Kristy Parsons, Joerg Mattes, Nathan W. Bartlett, Luke Hatchwell, Jason Girkin |
| Rok vydání: |
2014 |
| Předmět: |
|
| Zdroj: |
Respirology. 19:13-15 |
| ISSN: |
1323-7799 |
| DOI: |
10.1111/resp.12262_2 |
| Popis: |
Introduction:Some asthmatics display impaired type 1 IFN responses and exaggerated inflammatory responses upon Rhinovirus (RV) infection, however, the molecular basis for these observations remain obscure despite intensive research. Recently, impaired production of antiviral molecules and IFN-induced cytokines have been described in asthmatics when peripheral bloodmononuclear cells (PBMC) were stimulated with the TLR7 agonist Imiquimod but not in response to the TLR3 agonist poly I : C (Roponen et al. ERJ 2009). Interestingly, some asthmatics display variations in their TLR7 genotype that may be related to impaired TLR7 function. Aim:To identify the molecular basis for the aberrant response to RV observed in asthmatics. Method:Bronchial biopsies were taken from well characterized asthmatics and healthy controls. Expression of key pathogen recognition receptors including TLR3 and 7 were enumerated using qPCR. WT and TLR7-/- BALB/c mouse models of RV1B induced exacerbation of house dust mite driven allergic airways disease were employed to determine the relevance of TLR7 signallingin antiviral responses and inflammation. Results:Expression of TLR7 was found to be significantly reduced in bronchial biopsies from eosinophilic but not neutrophilic asthmatics. TLR7-/- mice were found to have a deficient response to RV1B infection with reduced levels of type I and III interferons and elevated viral titre at 24 hr post infection when compared to wild type controls. Treatment with type I or type III interferons limited RV1B replication as well as impaired both neutrophilic and eosinophilic inflammation.Conclusion:Our study suggests deficient TLR7 function as a crucial mechanism underpinning impaired IFN responses to RV1B in allergic airways inflammation. Restoration of IFN not only reduced viral replication but also impaired RV1B-induced inflammation. These studies may indicate that augmentation of TLR7-regulated effector functions could be exploited as a novel therapeutic approach for the treatment of virus-induced asthma exacerbation in asthmatics with deficient IFN responses and/or eosinophilic inflammation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
Plný text