Background Asthma 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.
Objectives To 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.
Methods Wild-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).
Results Allergic 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.
Conclusions This 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 eosinophiltargeting
treatments for the prevention of asthma
exacerbations.