Severe respiratory syncytial virus (RSV) infection is strongly associated with the development of childhood asthma. Also, infection with RSV increases allergen-specific IgE levels and may contribute to the heightened atopy reported in patients suffering severe RSV disease. The objectives of this application are to study the inter-relationship between RSV-induced and allergically-mediated bronchospasm and define the mechanisms by which RSV increases the allergic inflammatory response. The applicant and mentor have developed a model of RSV infection in ovalbumin sensitized mice in which methacholine-induced airway responsiveness is potentiated compared to the airway responsiveness seen in viral infection or allergen sensitization alone. They have also shown that RSV heightens allergen sensitization. Thus, two features of viral interaction with human disease, asthma and atopy, have been modelled in their murine system. They now propose to: 1) define the immunologic mechanisms by which ovalbumin sensitization potentiates methacholine-induced airway responsiveness in RSV infected mice; 2) define the immunologic mechanisms by which RSV infection increases the allergic response to ovalbumin sensitization; and 3) define the effect of prior RSV-specific immunization on the methacholine-induced airway responsiveness caused by the combination of ovalbumin sensitization and RSV infection. They hypothesize that both allergen potentiation of RSV-induced airway hyperresponsiveness and RSV potentiation of atopy are mediated by altered IL-4 regulation.
In Aim 1 they will sensitize mice to ovalbumin by a standard method of intraperitoneal injection and aerosolization, and then deplete IL-4 by antibody treatment at the time of RSV infection. They will also use a variety of immunologic and pharmacologic interventions to alter factors that affect IL-4 production. Endpoints will include: in vivo bronchial responsiveness to methacholine, illness, antigen-specific IgE levels, cytokine profiles in lung, RSV titers, and lung histopathology. Combining the animal models of virally-induced and allergically-mediated bronchospasm offers the opportunity to study the relationship between these two distinct causes of airway hyperreactivity.
In Aim 2 the interventions will be performed after RSV infection, but prior to the onset of aerosolized ovalbumin. Endpoints will be allergen-specific skin test responses in addition to those mentioned above.
In Aim 3 vaccination will be used to modulate the composition of the RSV-specific immune response to define its influence on virus-induced airway reactivity in an allergic host. These studies will allow us to better understand the relationships between viral disease, asthma, and atopy.
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