AADRC -- Mechanisms of Virus-Induced Asthma

University Of Wisconsin Madison, Madison WI

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Viral respiratory infections are the major cause of asthma exacerbations and, in some situations, may also contribute to the overall pathogenesis of asthma. It is the overall goal of our Asthma and Allergic Diseases Research Center (AADRC) to establish the mechanisms by which respiratory viruses can contribute to the pathogenesis of asthma. Central to this goal, it remains our hypothesis that a major mechanism in virus-induced asthma is the ability of respiratory viruses to cause or enhance airway inflammation. This occurs, it is believed, through the generation of proinflammatory cytokines and chemokines from resident airway cells, i.e., epithelial cells and airway macrophages, and the subsequent recruitment and activation of leukocytes, primarily neutrophils, in the airway to cause acute and, in some cases, persistent inflammation. In addition, it is hypothesized that a major mechanism of asthma pathogenesis and exacerbations from viral respiratory infections is a cytokine dysregulation, which is characterized by diminished T helper (Th)1 interferon (IFN)-gamma activity and enhanced Th2 responsiveness. To accomplish this overall goal, five areas of investigation are proposed. Project 1 will examine the hypothesis that diminished IFN-gamma production is a characteristic of some asthma patients, and this variant in cytokine generation enhances the severity of the infection, the generation of inflammatory mediators, and, consequently, an exacerbation of asthma in humans. Project 2 will determine the mechanisms responsible for IFN-gamma dysregulation in weaning Brown Norway rats by investigating the cellular, molecular, and developmental regulation of IFN-gamma by natural killer (NK) cells, CD8+ T cells, and CD4+ T cells. Project 3 will determine the intracellular signal transduction events in macrophages that occur with RV activation and how those signaling molecules regulate the generation of cytokines and experimental RV inoculation. Project 4 will test the hypothesis that RV infection of epithelial cells promotes interleukin (IL)-8 production by stabilizing IL-8 mRNA via MAP kinase signaling leading to interaction with AUUUA-binding proteins. Project 5 will characterize how products of viral respiratory infections, i.e., IL-8, modulate neutrophil function and how these consequences contribute to the generation of airway inflammation. A Core for Virology will provide virus preparations. It is proposed that these collaborative studies will provide new insight into mechanisms of respiratory-virus-induced asthma, the possible role of diminished IFN-gamma production in this process, and possibilities for new treatment.