Exposure to air pollutants, such as diesel exhaust (DE), is associated with airway inflammation, increased susceptibility to viral infection, and exacerbation of underlying respiratory disorders including allergic asthma. Based on studies in our laboratory and others, the mechanisms by which air pollutants cause these adverse effects likely involve alteration of inflammatory and antiviral signaling pathways linked to cellular oxidant/antioxidant imbalance. Since the previous grant we have expanded our experimental models to investigate 1.) how pre-existing allergic airway disease modifies the ability of DE to increase susceptibility to influenza, 2.) the role of NK cells and T cells in influenza-induced responses, and 3.) the effects of environmental pollutants on susceptibility to influenza virus in humans in vivo using inoculation with the live-attenuated influenza virus (LAIV) vaccine. We are therefore well positioned to test the hypotheses that exposure to DE increases allergic inflammation and susceptibility to influenza in humans, that oxidative stress-induced suppression of NK cell function mediates these effects, and that supplementation with SFN can prevent DE-induced alterations of antiviral immune responses.
Aim 1 will determine how DE exposure modifies inflammatory and antiviral responses to LAIV in normal volunteers and subjects with allergic rhinitis (AR). This will be a randomized, prospective comparison study comparing cohorts of normal or AR subjects randomized to receive either DE (100-300 (g/m3 x 2hr at rest) or placebo (clean air), followed by a standard dose of LAIV. Nasal lavage fluids and biopsies will be sampled at intervals during the resulting self-limited infection. Endpoints will include inflammatory mediators, antiviral factors, virus clearance, and effects of antioxidant genotype on exposure outcomes.
Aim 2 will determine how exposure to DE modifies NK and T cell activation in the context of influenza infection by assessing changes in activation, cytotoxic potential, and cytokine production (a) in nasal NK and T cells from subjects exposed to DE prior to infection with LAIV and (b) in in vitro models to further define potential mechanisms of DE-induced changes in NK cell activity.
Aim 3 will determine whether antioxidant supplementation with Sulforaphane (SFN) prevents the effects of DE exposure on virus-induced inflammation, antiviral defense response, and immune cell competence. These studies are expected to increase our understanding of whether and how DE enhances susceptibility to influenza virus, especially in the setting of allergic inflammation and the role of NK and T cells in these responses. We further anticipate that these studies will provide a model template useful for assessment of the impact of other environmental agents on respiratory mucosal defense in the context of viral infections, and for determination of the efficacy of intervention strategies.
This project will utilize a novel, safe, and currently approved protocol for controlled assessment of the combined effects of diesel exhaust and virus exposures on nasal inflammation in humans with allergic rhinitis in a real-life setting. Using samples obtained from volunteers this project will examine mechanisms by which exposure to air pollutants modify immune responses in humans. It will also test the impact of dietary antioxidants (sulforaphane-rich broccoli sprouts) on the nasal response to diesel exhaust and virus. Given the high frequency of exposures to diesel exhaust, the tendency of influenza to occur in large scale epidemics, and the high prevalence of allergic airway diseases, the potential scientific and public health impact of the project is large.
|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|
|Pawlak, Erica A; Noah, Terry L; Zhou, Haibo et al. (2016) Diesel exposure suppresses natural killer cell function and resolution of eosinophil inflammation: a randomized controlled trial of exposure in allergic rhinitics. Part Fibre Toxicol 13:24|
|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|
|Bauer, Rebecca N; Müller, Loretta; Brighton, Luisa E et al. (2015) Interaction with epithelial cells modifies airway macrophage response to ozone. Am J Respir Cell Mol Biol 52:285-94|
|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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