Exposure to particulate matter (PM) can significantly affect the susceptibility to infectious agents. Especially in urban environments, diesel exhaust (DE) emissions contribute to ambient PM levels. Despite vaccination efforts and antiviral treatments, respiratory virus infections, such as influenza virus infections, continue to be a significant threat to public health, especially in young children and the elderly. While the effects of DE or influenza virus alone have been studied in vitro and in vivo, the effects of acute or subchronic DE exposures on the susceptibility to subsequent influenza infections are largely unknown. Preliminary evidence suggests that exposure to DE increases influenza virus infections in epithelial cells in vitro and in mice in vivo and that these effects are not caused by suppressed interferon-dependent antiviral defense responses. Oxidative stress mediates many of the adverse effects induced by DE and addition of GSH was able to reverse the effects of DE extract (DEE) on influenza infections in vitro. Therefore, this project will expand our observations made in epithelial cells in vitro and examine the effects of acute and subchronic exposure to DE on influenza infections in mice in vivo and determine the role of oxidative stress in DE-induced modifications of influenza infections in vivo. Similar to our in vitro studies, this project plans to examine potential mechanisms involved in the increased influenza infections following DE exposures by concentrating on the effects of DE on the levels of collectins and the ability of resident macrophages to phagocytize influenza virus. Experiments conducted in vitro indicate that exposure to DEP increases influenza infections by enhancing influenza virus attachment within 2 hours post-infection. The experiments proposed here will examine potential mechansims involved in this response, focusing on oxidative modification and inactivation of collectins, as well as the enhanced ability to proteolytically activate the virus to enter the cell. Recent data suggests that in dendritic cells influenza-induced inflammatory cytokine production may depend on both toll-like receptor (TLR) 3 and TLR7. However, it is not clear whether TLR3, TLR7, or both are involved in influenza-induced responses in respiratory epithelial cells, which will be determined in this proposal. In addition, our in vitro data indicate that exposure to DEP enhances TLR3-dependent signaling by increasing the expression of TLR3 in respiratory epithelial cells. The experiments proposed here will build on this data and examine whether DE exposure enhances TLR3 or TLR7 levels and function in vivo and in vitro and determine the role of oxidative stress in these responses. Data derived from these experiments will provide important insights into the molecular mechanisms by which exposure to DE could enhance the susceptibility to influenza infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013611-02
Application #
7073999
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Mastin, Patrick
Project Start
2005-07-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$270,881
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Müller, Loretta; Meyer, Megan; Bauer, Rebecca N et al. (2016) Effect of Broccoli Sprouts and Live Attenuated Influenza Virus on Peripheral Blood Natural Killer Cells: A Randomized, Double-Blind Study. PLoS One 11:e0147742
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Dickinson, Alexandra J; Meyer, Megan; Pawlak, Erica A et al. (2015) Analysis of sphingosine kinase activity in single natural killer cells from peripheral blood. Integr Biol (Camb) 7:392-401
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Noah, Terry L; Zhang, Hongtao; Zhou, Haibo et al. (2014) Effect of broccoli sprouts on nasal response to live attenuated influenza virus in smokers: a randomized, double-blind study. PLoS One 9:e98671
Zavala, Jose; Lichtveld, Kim; Ebersviller, Seth et al. (2014) The Gillings Sampler--an electrostatic air sampler as an alternative method for aerosol in vitro exposure studies. Chem Biol Interact 220:158-68
Fischer 2nd, William A; Chason, Kelly D; Brighton, Missy et al. (2014) Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses during infection of human nasal epithelial cell cultures. Vaccine 32:1761-7
Meyer, Megan; Kesic, Matthew J; Clarke, John et al. (2013) Sulforaphane induces SLPI secretion in the nasal mucosa. Respir Med 107:472-5
Müller, Loretta; Brighton, Luisa E; Carson, Johnny L et al. (2013) Culturing of human nasal epithelial cells at the air liquid interface. J Vis Exp :
Müller, Loretta; Chehrazi, Claire V E; Henderson, Michael W et al. (2013) Diesel exhaust particles modify natural killer cell function and cytokine release. Part Fibre Toxicol 10:16

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