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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES010619-01
Application #
6191197
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Mastin, Patrick
Project Start
2000-09-30
Project End
2005-09-29
Budget Start
2000-09-30
Budget End
2001-09-29
Support Year
1
Fiscal Year
2000
Total Cost
$284,178
Indirect Cost
Name
Washington State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
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
Jin, Guang-Bi; Moore, Amanda J; Head, Jennifer L et al. (2010) Aryl hydrocarbon receptor activation reduces dendritic cell function during influenza virus infection. Toxicol Sci 116:514-22
Head, Jennifer L; Lawrence, B Paige (2009) The aryl hydrocarbon receptor is a modulator of anti-viral immunity. Biochem Pharmacol 77:642-53
Hogaboam, Jason P; Moore, Amanda J; Lawrence, B Paige (2008) The aryl hydrocarbon receptor affects distinct tissue compartments during ontogeny of the immune system. Toxicol Sci 102:160-70
Lawrence, B Paige; Denison, Michael S; Novak, Hermann et al. (2008) Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound. Blood 112:1158-65
Teske, Sabine; Bohn, Andrea A; Hogaboam, Jason P et al. (2008) Aryl hydrocarbon receptor targets pathways extrinsic to bone marrow cells to enhance neutrophil recruitment during influenza virus infection. Toxicol Sci 102:89-99
Neff-LaFord, Haley; Teske, Sabine; Bushnell, Timothy P et al. (2007) Aryl hydrocarbon receptor activation during influenza virus infection unveils a novel pathway of IFN-gamma production by phagocytic cells. J Immunol 179:247-55
Vorderstrasse, Beth A; Cundiff, Jennifer A; Lawrence, B Paige (2006) A dose-response study of the effects of prenatal and lactational exposure to TCDD on the immune response to influenza a virus. J Toxicol Environ Health A 69:445-63
Lawrence, B Paige; Roberts, Alan D; Neumiller, Joshua J et al. (2006) Aryl hydrocarbon receptor activation impairs the priming but not the recall of influenza virus-specific CD8+ T cells in the lung. J Immunol 177:5819-28
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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