Asthma is a common lung disease that is characterized by airway hyperreactivity and elevated levels of Immunoglobulin E (IgE) antibodies. It has become increasingly clear that viral infections are a significant factor in the induction and exacerbation of asthma. The common molecular mechanisms of viral-induced asthma, however, are not yet understood. It is hypothesized that viral-induced immunoglobulin class switching to IgE may be a mechanism for the association of viral infection with the induction of asthma. Infection with viral strains commonly associated with induction and exacerbation of asthma, leads to formation of double-stranded RNA (dsRNA) which consequently activates a ubiquitous anti viral protein kinase (Protein Kinase double-stranded RNA-activated, PKR). Based on preliminary data, PKR appears to be the pivotal signaling molecule in differentiation of the immune response toward the viral exacerbation of asthma. Furthermore, activation of PKR can lead to activation of the NFkB complex. This complex has been shown to be important for IgE class switching and IL-4 expression. To date, the influence of PKR activation on asthma has not been investigated. Thus, the application proposes to delineate the molecular mechanism by which viral infections lead to genetic regulation of IgE class switching.
The specific aims are to: 1a) Determine whether rhinovirus and respiratory syncytial virus (RSV), two viruses associated with human asthma activate PKR; b) By transfection of a negative dominant mutant, study the role of PKR in IgE class switching; c) Study the ability of viral-encoded inhibitors of PKR to alter/block viral-induced IgE class switching and cytokine expression; 2) Determine if dsRNA treatment favors Th2 cytokine profile in human B and T cells; 3) Study the viral and dsRNA induction of IgE protein synthesis; 4) Study the nuclear regulatory element in dsRNA-induced IgE class switching; and 5) Study the in vivo activation of PKR during rhinovirus infections in bronchoalveolar cells.
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