2014 Progress Report: Environmental Determinants of Early Host Response to RSV

EPA Grant Number: RD834515C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant RD834515
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Environmental Determinants of Early Host Response to RSV
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , White, Carl W. , Dakhama, Azzeddine , Yang, Jing , Loader, Joan , Correll, Kelly , Gabehart, Kelsa
Institution: National Jewish Health
Current Institution: National Jewish Health , National Jewish Medical and Research Center , University of Colorado at Denver , University of North Carolina at Charlotte
EPA Project Officer: Hahn, Intaek
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Period Covered by this Report: June 22, 2014 through June 21,2015
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The pollutant ozone is suspected to play a significant role in the development and exacerbation of reactive airway diseases such as asthma. Ozone exposure may alter lung development and growth, especially in the early postnatal development phase, resulting in increased susceptibility to airway obstruction upon subsequent viral infection and allergen exposure. Ozone exposure also can influence the innate immune response by increasing Toll-­like receptor (TLR)‐4 expression, thereby increasing airway responsiveness to bacterial endotoxin (LPS). LPS also is known to mature dendritic cells, the primary immune cell subset that initiates T-cell differentiation and directs the adaptive response. The overall hypothesis of this project is that ozone exposure, in the early postnatal phase, alters lung development and modifies the host immune response to early life viral infection and allergen exposure, thereby contributing to the development of reactive airway disease. In the presence of LPS, however, lung development will be sustained and the host immune response will mature and protect the newborn against the development of altered airway responses to viral infection and allergen exposure.

Specific Aim 1: To define the influence of ozone exposure on TLR expression and airway structure and function.

Specific Aim 2: To define the influence of ozone exposure on airway responsiveness to respiratory syncytial virus (RSV) and allergen.

Specific Aim 3: To determine if and how LPS can modify airway responsiveness to RSV infection and allergen, following postnatal exposure to ozone.

Progress Summary:

This project has made substantial progress in achieving its overall objective to characterize the influence of postnatal ozone exposure on TLR expression and on airway structure and function. To the best of our knowledge, this is the first study to profile the transcriptome response of the newborn lung to acute ozone exposure using genome-wide gene expression microarray analysis. The results identified several novel genes and molecular pathways never before associated with ozone exposure. The pattern of gene expression and the molecular pathways perturbed by ozone in the newborn lung are different from those described previously for adult (fully developed) lungs. Specifically, it was mainly cell cycle-associated functions, including cell division/proliferation, that were altered most significantly after acute ozone exposure in the developing newborn lung. It is not clear whether this suppression of the cell cycle/proliferation can lead to permanent damage to the lung (altered lung growth or altered structure and function) or if it is transient only, to allow repair of potentially damaged DNA from ozone exposure.

We also found that the airway response to ozone is age-dependent and this response is suppressed in the neonatal lung due to TLR-4 deficiency in this early age. The results also indicate that the neutrophilic airway response to ozone is dependent on TLR-4 signaling, whereas lung permeability is regulated by a mechanism independent of TLR-4 signaling. The role of neutrophils in ozone-mediated injury, whether pathogenic or protective, remains to be defined as planned in our future studies.

We also have focused on the effect airway hyperresponsiveness (AHR) of ozone on airway responsiveness to allergen exposure and RSV infection. Studies of the effects on allergen exposure showed that acute postnatal ozone exposure increased  AHR but not airway inflammation or antibody response to subsequent exposure to house dust mite. We are repeating these studies to confirm the findings and to determine if the increased AHR is mediated through a neurogenic mechanism (e.g., via substance P-NK1 receptor pathway). Studies of the effects of postnatal ozone exposure on response to RSV infection are in progress and will determine if ozone alters innate or adaptive immunity to viral infection. Ozone is known to alter the defense mechanisms of the lung against bacterial infection, but its effects on respiratory viral infection are largely unknown. Therefore, we expect to obtain new information that will improve our understanding of the host response to viral infection during exposure to common air pollutants.

Future Activities:

The coming year will include continuation of DAPS visits, analyses and preparation of our findings for presentation and manuscript submissions. Findings from our DAPS‐EPEM preliminary analyses were selected for presentation at the 2015 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section) and the 2015 American Thoracic Society International Conference, and are being developed for publication. For the NIH‐funded CAMP study, the Endotoxin Exposure Working Group completed its analyses, presented this work at the 2014 American Academy of Allergy, Asthma & Immunology Annual Meeting (Best of Environmental and Occupational Respiratory Diseases Interest Section), and is in the final stages of manuscript preparation for submission of their findings. We completed our collaborative investigation of endotoxin exposure and asthma outcomes in 150 inner-city children in Baltimore (NIH-funded MAACS Study: PI E. Matsui) and a manuscript of our findings was published. We also completed a collaborative investigation of endotoxin exposure and early childhood wheezing phenotypes in a Denver inner city pre-school cohort (NIH-funded CAPS Study). This was presented in 2014 at a premier meeting, and it is in the final stages of manuscript preparation for submission. What we have learned from our CAMP, EPEM, MAACS, HUD and CAPS studies, and the other Projects and COTC in our CEHC, has informed and strengthened DAPS.


Journal Articles on this Report : 13 Displayed | Download in RIS Format

Other subproject views: All 23 publications 13 publications in selected types All 13 journal articles
Other center views: All 51 publications 30 publications in selected types All 30 journal articles
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Journal Article Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, Leng L, Montgomery RR, Shaw A, Schwartz DA, Bucala R. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with gram-negative bacteremia in older adults. Journal of Infectious Diseases 2014;209(5):764-768. RD834515 (2013)
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  • Journal Article De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S. An evolutionarily conserved innate immunity protein interaction network. Journal of Biological Chemistry 2013;288(3):1967-1978. RD834515 (2013)
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  • Journal Article Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, Leach S, White CW, Dakhama A. Transcriptome profiling of the newborn mouse lung response to acute ozone exposure. Toxicological Sciences 2014;138(1):175-190. RD834515 (2011)
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  • Journal Article Gabehart K, Correll KA, Loader JE, White CW, Dakhama A. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respiratory Research 2015;16:117. RD834515 (2013)
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  • Journal Article Gao Z, Dosman JA, Rennie DC, Schwartz DA, Yang IV, Beach J, Senthilselvan A. NOS3 polymorphism, lung function, and exposure in swine operations: results of 2 studies. Journal of Allergy and Clinical Immunology 2014;134(2):485-488. RD834515 (2013)
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  • Journal Article Henao-Martinez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infection, Genetics and Evolution 2013;16:386-391. RD834515 (2013)
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  • Journal Article Jing J, Yang IV, Hui L, Patel JA, Evans CM, Prikeris R, Kobzik L, O'Connor BP, Schwartz DA. Role of macrophage receptor with collagenous structure in innate immune tolerance. Journal of Immunology 2013;190(12):6360-6367. RD834515 (2013)
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  • Journal Article Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, Hide W. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 2013;8(5):e62910. RD834515 (2013)
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  • Journal Article Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 2014;9(4):e93550 (10 pp.). RD834515 (2013)
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  • Journal Article Matsui EC, Hansel NN, Aloe C, Schiltz AM, Peng RD, Rabinovitch N, Ong MJ, Williams DL, Breysse PN, Diette GB, Liu AH. Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. American Journal of Respiratory and Critical Care Medicine 2013;188(10):1210-1215. RD834515 (2012)
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  • Journal Article Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, LaFlamme D, Jing J, Hui L, Schwartz DA, Yang IV. Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist. American Journal of Respiratory Cell and Molecular Biology 2013;48(1):27-34. RD834515 (2013)
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  • Journal Article Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. RD834515 (2013)
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  • Journal Article Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2011;45(2):393-402. RD834515 (2013)
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  • Supplemental Keywords:

    Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, human health, asthma indices, intervention, asthma triggers, allergic response, airway inflammation, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Biology, asthma, asthma triggers, sensitive populations, endotoxin, asthma indices, airway inflammation, children, allergic response

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011
  • 2012
  • 2013
  • 2015 Progress Report
  • Final

  • Main Center Abstract and Reports:

    RD834515    Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    RD834515C001 Endotoxin Exposure and Asthma in Children
    RD834515C002 Environmental Determinants of Early Host Response to RSV
    RD834515C003 Environmental Determinants of Host Defense