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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
Huang, Huaqiong; Saravia, Jordy; You, Dahui et al. (2015) Impaired gamma delta T cell-derived IL-17A and inflammasome activation during early respiratory syncytial virus infection in infants. Immunol Cell Biol 93:126-35
Cormier, Stephania A; Shrestha, Bishwas; Saravia, Jordy et al. (2014) Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection. J Virol 88:9350-60
Lee, Greg I; Saravia, Jordy; You, Dahui et al. (2014) Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection. Part Fibre Toxicol 11:57
Saravia, J; You, D; Thevenot, P et al. (2014) Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression. Mucosal Immunol 7:694-704
Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu et al. (2014) Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Crit Care Med 42:e692-701
Lomnicki, Slawo; Gullett, Brian; Stöger, Tobias et al. (2014) Combustion By-Products and their Health Effects--combustion engineering and global health in the 21st century: issues and challenges. Int J Toxicol 33:3-13
Thevenot, Paul T; Saravia, Jordy; Jin, Nili et al. (2013) Radical-containing ultrafine particulate matter initiates epithelial-to-mesenchymal transitions in airway epithelial cells. Am J Respir Cell Mol Biol 48:188-97
Wang, Pingli; You, Dahui; Saravia, Jordy et al. (2013) Maternal exposure to combustion generated PM inhibits pulmonary Th1 maturation and concomitantly enhances postnatal asthma development in offspring. Part Fibre Toxicol 10:29
Saravia, Jordy; Lee, Greg I; Lomnicki, Slawo et al. (2013) Particulate matter containing environmentally persistent free radicals and adverse infant respiratory health effects: a review. J Biochem Mol Toxicol 27:56-68
Thevenot, Paul; Saravia, Jordy; Giaimo, Joseph et al. (2013) Chronic alcohol induces M2 polarization enhancing pulmonary disease caused by exposure to particulate air pollution. Alcohol Clin Exp Res 37:1910-9

Showing the most recent 10 out of 23 publications