Rhinovirus-Induced Exacerbations of Asthma and COPD

Hershenson, Marc B.

To test the hypothesis that the immune response to rhinovirus may be counterproductive, we infected mice with defects in TLR and MDA-5 [89] , molecules which recognize double-stranded RNA on the cell surface or in the cell cytoplasm, respectively. As noted above, these signaling pathways are responsible for double-stranded RNAstimulated interferon production. Our previous work showed that MDA-5, an RNA helicase, is required for rhinovirusinduced interferon production in cultured airway epithelial cells [73] . TLR3 knockout mice had normal interferon responses to rhinovirus infection. However, MDA5 knockout mice showed a delay in type I interferon responses and a significant and persistent reduction in type III interferon lambda production. However, despite these deficiencies, MDA5 knockout mice showed only small increases in RV vRNA and titer. Further, RV-infected knockout mice showed less, rather than more, airway inflammation. Similar results were found in rhinovirus-infected ovalbumin-sensitized and -challenged knockout mice. These data call into question the interferon requirement for RV clearance and suggest that the proinflammatory response to rhinovirus infection is indeed maladaptive. Indeed, a recent study found that interferonlambda concentrations were higher in rhinovirus-infected infants with wheezing compared to those without wheezing [108] .