Abstract

The overall goal of this proposal is to determine how specific genetic, biologic, and immunologic characteristics interact to predispose individuals to develop asthma. In that context, we propose to study a select population of infants with respiratory syncytial virus (RSV) bronchiolitis who are at substantial risk of developing asthma. RSV infection in the first year of life is a substantial risk factor for the development of persistent wheezing. The interaction of RSV with the host epithelial-immune system and underlying genetic background is unclear. Accordingly, Aim I proposes to evaluate the association between an atopic genotype, the R576 IL-4 alpha receptor mutation, and the development of an asthmatic phenotype in a prospective cohort of infants with RSV bronchiolitis. Given the appropriate risk factors, RSV illicits an immune response characterized by inflammatory cell influx, especially T cells, into the airway. Accordingly Aim II proposes to evaluate the effect of airway inflammation, demonstrated by persistent expression of the beta chemokine, RANTES, in airway epithelial cells, in a prospective cohort of infants with RSV bronchiolitis who are at risk of developing an asthmatic phenotype. This possibility is supported by evidence of increased RANTES expression (by mRNA stabilization) in human tracheal epithelial cells infected with RSV in vitro and in upper airway epithelial cells from infants with RSV bronchiolitis. The T cell immune response following viral infection appears to be primarily Thl-type, however in the setting of RSV bronchiolitis this is less clear. Accordingly, Aim III proposes to assess the T cell profile,, Th1 vs. Th2 phenotype, as defined by cytokine expression and other phenotypic markers, in a prospective cohort of infants with RSV bronchiolitis who are at risk of developing an asthmatic phenotype. Therefore, this proposal will lead to a better understanding of the interaction of genetic, biologic, and immunologic factors following RSV infection which lead to the development of asthma in early life.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061895-02
Application #
6078061
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Project Start
1998-09-30
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Ehlers, A; Xie, W; Agapov, E et al. (2018) BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes. Mucosal Immunol 11:97-111
Kitcharoensakkul, Maleewan; Bacharier, Leonard B; Yin-Declue, Huiqing et al. (2016) Temporal biological variability in dendritic cells and regulatory T cells in peripheral blood of healthy adults. J Immunol Methods 431:63-5
Zhou, Yanjiao; Bacharier, Leonard B; Isaacson-Schmid, Megan et al. (2016) Azithromycin therapy during respiratory syncytial virus bronchiolitis: Upper airway microbiome alterations and subsequent recurrent wheeze. J Allergy Clin Immunol 138:1215-1219.e5
Torgerson, Dara G; Giri, Tusar; Druley, Todd E et al. (2015) Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy. PLoS One 10:e0142649
Bacharier, Leonard B; Cohen, Rebecca; Schweiger, Toni et al. (2012) Determinants of asthma after severe respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol 130:91-100.e3
Silver, Eli; Yin-DeClue, Huiqing; Schechtman, Ken B et al. (2009) Lower levels of plasmacytoid dendritic cells in peripheral blood are associated with a diagnosis of asthma 6 yr after severe respiratory syncytial virus bronchiolitis. Pediatr Allergy Immunol 20:471-6
Castro, Mario; Schweiger, Toni; Yin-Declue, Huiquing et al. (2008) Cytokine response after severe respiratory syncytial virus bronchiolitis in early life. J Allergy Clin Immunol 122:726-733.e3
Bradley, Joseph P; Bacharier, Leonard B; Bonfiglio, JoAnn et al. (2005) Severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy. Pediatrics 115:e7-14
Cohen, Lance; Castro, Mario (2003) The role of viral respiratory infections in the pathogenesis and exacerbation of asthma. Semin Respir Infect 18:3-8