Rhinoviruses, the cause of common colds, are the most frequent precipitants of acute exacerbations of asthma and COPD3–7
, as well as causes of other serious respiratory diseases1,2
. The mouse models of minor- and major-group rhinovirus infection reported herein are characterized by several relevant disease-related outcomes, including airway neutrophilic and lymphocytic inflammation16,17
, mucin secretion (a cardinal symptom of common colds that is also induced by rhinovirus infection of human airway epithelial cells in vitro18
) and the induction of various chemokines and proinflammatory cytokines induced in human rhinovirus infections.
Our recent work has highlighted deficient induction of IFN-β and IFN-λ in lung cells from asthmatic donors in response to rhinovirus infection ex vivo19,20
. However, the relative importance of the IFN subtypes in rhinovirus infections is unknown, and although IFN-λ1 has been shown to have antiviral effects21,22
, it has not been known whether IFN-λs are produced by rhinovirus infections in vivo
. Our data suggest that IFN-λ is the most sustained and abundant IFN subtype induced in the lung by rhinovirus infections.
The absence of pathologic, physiologic or antiviral responses in mice inoculated with UV-inactivated virus and in nontransgenic mice inoculated with rhinovirus-16 indicates that these responses were replication dependent. Replication was studied further with in situ
hybridization, which showed early production of negative-sense replicative RNA and subsequent synthesis of viral genomic RNA in epithelial cells, which is consistent with the rhinovirus replication cycle. We observed further evidence of viral replication in the increased levels of rhinovirus-16 RNA in the lungs of transgenic mice compared to those in control mice and in the induction of type 1 IFN-α and IFN-β and type 3 IFN-λs. The use of viruses better adapted for replication in mice23,24
or different mouse strains, including those with deficient IFN responses19,20
, may allow for better virus replication in mice.
Because rhinoviruses are the major precipitants of acute exacerbations of asthma3–6
, we studied the interactions between rhinovirus infection and allergic airway inflammation. In allergen-sensitized and allergen-challenged mice, rhinovirus infection exacerbated neutrophilic, eosinophilic and lymphocytic airway inflammation, airway hyper-responsiveness, mucus secretion and production of both T helper type 1 (TH
1) and TH
2 cytokines. These responses have been associated with rhinovirus-induced exacerbations of asthma25
, including fatal asthma26
, and are consistent with either rhinovirus infection substantially exacerbating allergic airway inflammation or, conversely, allergic airway inflammation substantially exacerbating rhinovirus-induced inflammation.
The mechanisms involved in the synergistic interaction between virus infection and allergen exposure to increase the risk of asthma exacerbations are unknown27,28
2-mediated inflammation is clearly implicated in allergic airway inflammation; however, it is not known whether rhinovirus infection can augment TH
2 responses to allergens. Conversely, virus infection is strongly associated with TH
1 responses, but it is not known whether allergic airway inflammation can augment rhinovirus-induced TH
1 responses. We show here that rhinovirus infection increases production of both IL-4 and IL-13 in response to allergen challenge, indicating that rhinovirus infection can exacerbate TH
2 responses to allergens. Similarly, allergen challenge increased rhinovirus induction of IFN-γ, confirming that allergen exposure can enhance TH
1 responses to rhinoviruses. Further studies will be required to increase our understanding of these possible mechanisms of disease to aid the development of new therapeutic approaches.
In conclusion, these models of rhinovirus infection should be useful in investigating the pathogenesis and treatment of the common cold and acute exacerbations of asthma. With further development, they will probably provide a similar boost to research into exacerbations of COPD7
and other diseases in which rhinovirus infection is implicated2