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 #
3R01HL095163-03S1
Application #
8307709
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
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$57,190
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
Jensen, Majken K; Aroner, Sarah A; Mukamal, Kenneth J et al. (2018) High-Density Lipoprotein Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts. Circulation 137:1364-1373
Budoff, Matthew J; Young, Rebekah; Burke, Gregory et al. (2018) Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J 39:2401-2408
Osawa, Kazuhiro; Nakanishi, Rine; McClelland, Robyn L et al. (2018) Ischemic stroke/transient ischemic attack events and carotid artery disease in the absence of or with minimal coronary artery calcification: Results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 275:22-27
Leary, Peter J; Kronmal, Richard A; Bluemke, David A et al. (2018) Histamine H2 Receptor Polymorphisms, Myocardial Transcripts, and Heart Failure (from the Multi-Ethnic Study of Atherosclerosis and Beta-Blocker Effect on Remodeling and Gene Expression Trial). Am J Cardiol 121:256-261
Dunn, Erin C; Sofer, Tamar; Wang, Min-Jung et al. (2018) Genome-wide association study of depressive symptoms in the Hispanic Community Health Study/Study of Latinos. J Psychiatr Res 99:167-176
Ohyama, Yoshiaki; Redheuil, Alban; Kachenoura, Nadjia et al. (2018) Imaging Insights on the Aorta in Aging. Circ Cardiovasc Imaging 11:e005617
Rao, Vishal N; Zhao, Di; Allison, Matthew A et al. (2018) Adiposity and Incident Heart Failure andĀ its Subtypes: MESA (Multi-Ethnic Study of Atherosclerosis). JACC Heart Fail 6:999-1007
Judson, Gregory L; Rubinsky, Anna D; Shlipak, Michael G et al. (2018) Longitudinal Blood Pressure Changes and Kidney Function Decline in Persons Without Chronic Kidney Disease: Findings From the MESA Study. Am J Hypertens 31:600-608
Ladeiras-Lopes, Ricardo; Moreira, Henrique T; Bettencourt, Nuno et al. (2018) Metabolic Syndrome Is Associated With Impaired Diastolic Function Independently of MRI-Derived Myocardial Extracellular Volume: The MESA Study. Diabetes 67:1007-1012
Al Rifai, Mahmoud; Greenland, Philip; Blaha, Michael J et al. (2018) Factors of health in the protection against death and cardiovascular disease among adults with subclinical atherosclerosis. Am Heart J 198:180-188

Showing the most recent 10 out of 382 publications