Previous studies have demonstrated that the incidence and severity of respiratory virus infections is greater in smokers than in non-smokers, but the mechanisms mediating these responses are currently not well understood. Our preliminary data demonstrate that cultured nasal epithelial cells from smokers are more susceptible to influenza virus infections, shed more virus, and have decreased expression of type 1 interferons. This in vitro model thus provides an important tool to investigate the cellular and molecular basis for enhanced susceptibility to influenza virus seen in smokers. In addition, our preliminary data demonstrate that nasal administration of live attenuated influenza virus (LAIV) offers the possibility of studying influenza virus infections safely in humans in vivo. Using tightly linked human in vitro and in vivo approaches, this proposal is designed to test the hypothesis that chronic exposure to cigarette smoke alters epithelial antiviral and inflammatory responses to influenza virus infection via two potentially related mechanisms: decreased expression of phase II (antioxidant) enzymes and suppression of type 1 interferon (antiviral) pathways. We further hypothesize that upregulation of phase II enzymes via nutritional supplementation with SFN is a potential therapeutic strategy to mitigate these effects.
Specific Aim 1 will use an in vitro model of differentiated human nasal epithelial cells to determine mechanisms that modify influenza-induced antiviral defense responses in smokers, initially focusing on the role of type I IFN antiviral defense responses and the potential role of cigarette smoke-induced gene silencing.
Specific Aim 2 will use our existing protocol of administration of LAIV vaccine as a model for influenza virus infections to confirm mechanisms that mediate enhanced susceptibility to influenza infections in smokers in vivo. LAIV-induced viral replication and antiviral defense responses will be assessed in smokers and non-smokers using endpoints measured in nasal biopsy tissue and lavage fluids. Outcomes within each study cohort will be grouped based on changes in innate immune defense gene expression found in Specific Aim 1.
Specific Aim 3 will use both the in vitro and in vivo models to determine the relationships between antioxidant gene expression, antiviral pathways, and virus-induced inflammation in smokers and non-smokers. We will assess how upregulation of HO-1 as a result of supplementation with SFN can improve key abnormalities in antiviral pathways and inflammatory/immune response changes associated with smokers, as identified in Specific Aims 1 and 2. Data derived from these studies will yield insights into the mechanisms that enhance the susceptibility to influenza virus infections in smokers and explore potential therapeutic interventions using a translational research design.

Public Health Relevance

Susceptibility to and severity of influenza infections is enhanced in smokers, but the mechanisms mediating this effect are largely unknown. We have established human in vitro and in vivo experimental models of influenza infections, which will be applied to determine cellular and molecular mechanisms mediating enhanced susceptibility to influenza virus in smokers and to explore potential therapeutic interventions. Knowledge obtained from these studies can be exploited to develop new therapeutic strategies aimed at mitigating respiratory virus infections and their effects in individuals chronically exposed to tobacco smoke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095163-02
Application #
7914195
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Noel, Patricia
Project Start
2009-08-12
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$370,000
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
Bhambhani, Vijeta; Kizer, Jorge R; Lima, Joao A C et al. (2018) Predictors and outcomes of heart failure with mid-range ejection fraction. Eur J Heart Fail 20:651-659
Vella, Chantal A; Cushman, Mary; Van Hollebeke, Rachel B et al. (2018) Associations of Abdominal Muscle Area and Radiodensity with Adiponectin and Leptin: The Multiethnic Study of Atherosclerosis. Obesity (Silver Spring) 26:1234-1241
Raffield, Laura M; Ellis, Jaclyn; Olson, Nels C et al. (2018) Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study. J Hum Genet 63:327-337
Cainzos-Achirica, Miguel; Miedema, Michael D; McEvoy, John W et al. (2018) The prognostic value of high sensitivity C-reactive protein in a multi-ethnic population after >10?years of follow-up: The Multi-Ethnic Study of Atherosclerosis (MESA). Int J Cardiol 264:158-164
Floyd, J S; Sitlani, C M; Avery, C L et al. (2018) Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 18:127-135
Mortensen, Martin Bødtker; Falk, Erling; Li, Dong et al. (2018) Statin Trials, Cardiovascular Events, and Coronary Artery Calcification: Implications for a Trial-Based Approach to Statin Therapy in MESA. JACC Cardiovasc Imaging 11:221-230
Ricalde, Aldrich; Allison, Matthew; Rifkin, Dena et al. (2018) Anthropometric measures of obesity and renal artery calcification: Results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 271:142-147
Hajek, Catherine; Guo, Xiuqing; Yao, Jie et al. (2018) Coronary Heart Disease Genetic Risk Score Predicts Cardiovascular Disease Risk in Men, Not Women. Circ Genom Precis Med 11:e002324
Marques, Mateus D; Nauffal, Victor; Ambale-Venkatesh, Bharath et al. (2018) Association Between Inflammatory Markers and Myocardial Fibrosis. Hypertension 72:902-908
Aladin, Amer I; Al Rifai, Mahmoud; Rasool, Shereen H et al. (2018) Relation of Coronary Artery Calcium and Extra-Coronary Aortic Calcium to Incident Hypertension (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 121:210-216

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