Rhinovirus-Induced Exacerbations of Asthma and COPD

Hershenson, Marc B.

Returning to the problem of animal models, major group viruses do not bind to murine cells, owing to a lack of homology between the human and mouse ICAM-1. However, it was subsequently shown that minor group viruses infect LA-4 mouse tracheal epithelial cells [88] . We [68] [69] [70] [71] [72] 89] and others [90] therefore infected mice with a minor group virus, RV1B, by the intranasal route. Because of as-yet undefined factors which limit viral replication in the mouse, infection is followed by a steady reduction in viral copy number and titer. However, careful studies of viral copy number show a spike in positive-strand vRNA approximately 24 hours after infection and a small amount of negative-strand vRNA indicating viral replication. We also found a robust interferon response to infection, implying viral replication. Immunofluorescence showed infection of airway epithelial cells and, interestingly, occasional subepithelial cells resembling monocytes. Airways of infected mice showed neutrophilic inflammation which decreased with time, as well as subsequent lymphocytic infiltration, a pattern classically associated with viral infection. When we examined respiratory system resistance changes in response to methacholine administration, we found a small but significant increase in airways responsiveness in rhinovirus-infected mice which persisted at least four days after infection. Interestingly, mice infected with UVirradiated replication-deficient virus showed modest airway inflammation and responsiveness one, but not four, days after infection. These data suggest that rhinovirus could induce a state of airways hyperresponsiveness without viral replication in the lungs, at least under some circumstances. Consistent with this, UV irradiation inhibits but does not abolish major group RV-induced IL-8 release in cultured airway epithelial cells [43, 91, 92] .