It has become increasingly clear that viral infections are a significant factor in the induction and acute exacerbation of allergic inflammation such as asthma. We originally hypothesized that viral-induced immunoglobulin class switching to IgE was a mechanism for the association of viral infections with the induction of asthma. Our accumulated data support this hypothesis. 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 that is activated by double-stranded RNA, PKR). Our data show that based on the concentration, dsRNA can induce cytokines that are consistent with both Th1 or Th2 phenotypes. PKR appears to be the pivotal signaling molecule in differentiation of the immune response toward a Th2 phenotype and IgE class switching. We will further characterize this observation by examining the molecular pathways that are activated during infections with respiratory viruses that can induce IL-4 or IFN-g. In addition to the induction of allergic reactions by increasing IgE expression, viral infections are a significant factor in the acute exacerbation of childhood asthma and asthma-related deaths. The viral-induced asthma exacerbation is secondary to activation of innate immune responses by induction of inflammatory cytokines and chemokines. Airway epithelial cells are the initial target of respiratory viruses and two critical inflammatory cytokines that are generated during viral infections are TNF-a and IL-1b_ Our data show that viral induction of TNF-a and IL-1b_follow divergent signaling pathways. Our published data show that PKR activation in bronchial epithelial cells regulates TNF-a but not IL-1b. The outcome of these studies will provide insight into the molecular mechanisms of viral induced allergic inflammation.
| Witt, Kristine L; Tice, Raymond R; Wolfe, Gary W et al. (2004) Genetic damage detected in CD-1 mouse pups exposed perinatally to 3'-azido-3'-deoxythymidine or dideoxyinosine via maternal dosing, nursing, and direct gavage: II. Effects of the individual agents compared to combination treatment. Environ Mol Mutagen 44:321-8 |
| Bishop, Jack B; Tani, Yoshiro; Witt, Kristine et al. (2004) Mitochondrial damage revealed by morphometric and semiquantitative analysis of mouse pup cardiomyocytes following in utero and postnatal exposure to zidovudine and lamivudine. Toxicol Sci 81:512-7 |
