The overall goal of this application is to determine how specific genetic, biologic, and immunologic characteristics interact to predispose individuals to develop asthma. In that context, over the last three years, we have developed a carefully selected cohort of 206 infants with respiratory syncytial virus (RSV) bronchiolitis (the RBEL (RSV Bronchiolitis in Early Life) cohort) who are at substantial risk of developing asthma. Surprisingly, physicians have already diagnosed asthma in 40 percent of the children in the RBEL cohort. The children have had at least one year of follow-up. This project builds upon our previous work establishing the largest prospective U.S. study children with RSV bronchiolitis severe enough to require hospitalization and proposes that this study should be continued for an additional five years in order to more definitively establish the diagnosis of asthma in this cohort. 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 genotypes associated with atopy, the IL-4 receptor a and IL- 13 single nucleotide polymorphisms, and the development of an asthmatic phenotype in the RBEL cohort of children. Given the appropriate risk factors, RSV elicits an immune response characterized by inflammatory cell influx, especially T cells, into the airway. Accordingly, Aim II proposes to evaluate the effect of airway epithelial inflammation, demonstrated by persistent RANTES (Regulated upon Activation, Normal T-cell Expressed) expression in airway epithelial cells, on the development of an asthmatic phenotype in the RBEL cohort of children. 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 RBEL infants with RSV bronchiolitis. The T cell immune response following viral infection appears to be primarily Th1-type; however, in the setting of RSV infection, there actually may be a skewing of the immune response to a Th2 phenotype early in life. Accordingly, Aim III proposes to evaluate prospectively the T cell profile, Th1 vs. Th2 phenotype, as defined by cytokine expression and other phenotypic markers, in the RBEL cohort of children who are at risk of developing an asthmatic phenotype. Therefore, this application will lead to a better understanding of the interaction of genetic, biologic, and immunologic factors following serious RSV infection which lead to the development of asthma in early life. Furthermore, we propose to develop an asthma predictive index for children with serious RSV infection based upon the findings of the studies outlined in this application. Such an index would be extremely valuable to clinicians taking care of children following a severe RSV infection to provide prognostic information and to identify children at highest risk for the development of asthma who may benefit from an early intervention or treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061895-09
Application #
7111064
Study Section
Special Emphasis Panel (ZRG1-EDC-3 (01))
Program Officer
Noel, Patricia
Project Start
1998-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
9
Fiscal Year
2006
Total Cost
$373,511
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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