Halogenated aromatic hydrocarbons (HAH) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are abundant environmental contaminants, which elicit their toxic, and biological effects by binding to a ligand-activated transcription factor, the Ah receptor, and inappropriately alter gene expression. It is well established that RAH are potent immunosuppressive agents, affecting both humoral and cell-mediated immunity. In fact, the most sensitive adverse effect of TCDD reported to date is increased mortality following respiratory infection of mice with influenza virus. However, few studies have been performed to determine the mechanism by which exposure to TCDD causes this enhanced mortality, and the immunotoxic mechanism and direct cellular targets of TCDD are unknown. Furthermore, very few studies have examined the effects of TCDD on the lung or pulmonary immune system. The immune response to influenza virus is complex and requires cells and cellular products from the innate, humoral and cell-mediated arms of the immune system. Given the prevalence of respiratory infections in the human population and the possible adverse human health effects due to HAH, it is vital that we understand the mechanism of toxicity and the specific effects of HAH on anti-viral immunity to respiratory infection with influenza virus. A murine model of human influenza A virus infection offers an experimental system with exquisite sensitivity to TCDD and direct relevance to human health, providing a system for mechanistic studies to better understand how exposure to these abundant, highly toxic and persistent pollutants affects protective immunity to viral infection. In preliminary studies, exposure of mice to TCDD was shown to suppress influenza-specific antibody production, diminish CTL generation and alter cytokine production. The goal of the proposed studies is to test the hypothesis that exposure to TCDD increases susceptibility to influenza virus by altering cytokine production by the innate immune system, leading to cytokine-mediated pathology and suppression of adaptive immunity.
The Specific Aims of this grant are to (1) identify the mechanisms responsible for cytolytic activity and viral clearance in TCDD-treated mice, (2) further characterize the effects of TCDD on cytokine production in the lung, (3) identify the cellular target(s) of TCDD immunotoxicity in the lung, (4) establish the functional relationship between changes in cytokine levels and suppressed adaptive immunity, and (5) determine the role of the Ah receptor in decreased host resistance to influenza virus.
|Wheeler, Jennifer L Head; Martin, Kyle C; Lawrence, B Paige (2013) Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection. J Immunol 190:659-68|
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|Vorderstrasse, Beth A; Lawrence, B Paige (2006) Protection against lethal challenge with Streptococcus pneumoniae is conferred by aryl hydrocarbon receptor activation but is not associated with an enhanced inflammatory response. Infect Immun 74:5679-86|
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