Epidemiological data support a causal link between exposure to elevated levels of particulate matter (PM) and increased lower respiratory tract infections (LRTIs) in children. During the H1N1 influenza (Flu) pandemic, exposure to PM was a potential contributing factor to the disparity in the increased levels of H1N1-induced morbidity and mortality observed in Mexico and the United States. Interestingly, the risk of LRTIs due to PM exposure is highest in infants. Despite strong evidence associating PM exposure and LRTI susceptibility, morbidity, and mortality in infants;there is very little research on this subject nd the mechanisms underlying this phenomenon are unknown. We have developed a novel neonatal (<7d of age) rodent model for studying PM exposures, which we apply here to understand the effects of PM on enhanced susceptibility to LRTI and LRTI-mediated disease severity. We show that age of exposure to PM is important in predicting LRTI disease sequela and that infant exposure to PM initiated several events that may explain the epidemiological data. First, exposure of neonatal mice to PM results in epithelial disruption. Second, adaptive immune responses following PM exposure in neonates are suppressive in nature (i.e. increased IL10 and Treg cells and decreased Th1, Tc1, and Th17 cell numbers) and not protective. The end result is enhanced severity of Flumediated disease as evidenced by increased pulmonary viral loads and mortality in neonatal mice infected following exposure to PM. Our data further suggest that PM-induced epithelial signals either cell associated or secreted (i.e. epimmunome) are used to direct this aberrant immune response to Flu by programming dendritic cells (DCs). Thus, we hypothesize that exposure to PM during infancy increases the severity of infectious respiratory disease through a process involving alteration of the epimmunome.
Aim 1 will test the hypothesis that neonatal exposure to PM suppresses pulmonary host defense against Flu and enhances disease.
Aim 2 will define downstream regulatory T cell mechanisms induced by PM exposure which suppress the immune response to Flu. Our preliminary data indicate a role for IL10 and regulatory T cells in enhanced Flu-mediated disease. We will first determine the source of PM-induced IL10 using reporter mice and examine the necessity for IL10 in PM exposure enhanced Flu severity using IL10 deficient mice and IL10 reconstitution experiments.
Aim 3 will determine the upstream signals from PM altered airway epithelium that dictate dendritic cell (DC) phenotype which in turn influences T cell responses. These studies will be accomplished using DC specific ?-catenin knockout mice and our recently developed neonatal epithelial:DC co-culture system to explore the role of ?-catenin signaling in DC function. Completion of these studies will provide us with an understanding of the molecular signaling events between injured epithelial cells and DCs crucial to understand how PM exposure alters Flu pathogenesis in infants and to identify pharmacologic targets for the treatment of environmentally-induced asthma exacerbations due to LRTI.

Public Health Relevance

Elevated levels of PM increase risk of infant mortality from lower respiratory tract infections such as influenza;and yet, few studies have tried to understand the mechanisms responsible for increased risk for LRTIs in this population following exposure to PM. Despite these facts, there is an urgent need for research in this area to understand the public health risks and develop therapeutic interventions. The concepts established here will have important implications for understanding mechanisms of PM-mediated airway disease and for understanding mechanisms of the epimmunome relevant to reducing morbidity and mortality associated with PM-exacerbated LRTI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015050-09
Application #
8723588
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
2006-09-01
Project End
2017-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
9
Fiscal Year
2014
Total Cost
$311,300
Indirect Cost
$103,767
Name
University of Tennessee Health Science Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Dugas, Tammy R; Lomnicki, Slawomir; Cormier, Stephania A et al. (2016) Addressing Emerging Risks: Scientific and Regulatory Challenges Associated with Environmentally Persistent Free Radicals. Int J Environ Res Public Health 13:
Oyana, Tonny J; Matthews-Juarez, Patricia; Cormier, Stephania A et al. (2016) Using an External Exposome Framework to Examine Pregnancy-Related Morbidities and Mortalities: Implications for Health Disparities Research. Int J Environ Res Public Health 13:ijerph13010013
Schwingshackl, Andreas; Kimura, Dai; Rovnaghi, Cynthia R et al. (2016) Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial. Cytokine 77:63-71
Stephenson, Erin J; Ragauskas, Alyse; Jaligama, Sridhar et al. (2016) Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice. Am J Physiol Endocrinol Metab 310:E1003-15
You, Dahui; Saravia, Jordy; Siefker, David et al. (2016) Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants. J Virol 90:2-4
Chen, Zhi-Hua; Wu, Yin-Fang; Wang, Ping-Li et al. (2016) Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium. Autophagy 12:297-311
Nau Jr, Felix; Miller, Justin; Saravia, Jordy et al. (2015) Serotonin 5-HTâ‚‚ receptor activation prevents allergic asthma in a mouse model. Am J Physiol Lung Cell Mol Physiol 308:L191-8
Sussan, Thomas E; Gajghate, Sachin; Thimmulappa, Rajesh K et al. (2015) Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One 10:e0116861
Hrincius, Eike R; Liedmann, Swantje; Finkelstein, David et al. (2015) Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway. Cell Rep 11:1591-603
Schwingshackl, Andreas; Meduri, Gianfranco Umberto; Kimura, Dai et al. (2015) Corticosteroids in pediatric ARDS: all cards on the table. Intensive Care Med 41:2036-7

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