The long term objective of this application is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. There is abundant evidence that children who experience severe RSV bronchiolitis during infancy are at greater risk for developing asthma later in childhood;however the host and viral determinants of severity of illness are not fully defined. Also unknown is whether mild RSV-induced illness in infancy may protect against the subsequent development of childhood asthma. In Project 1, we utilize the ReSPIRA (Respiratory Study for Protection of Infants from RSV to Asthma) cohort of 2000 infants to focus on host immune responses to RSV infection and the subsequent risk of recurrent wheezing and childhood asthma. Specifically, in Project 1 we will a) establish the relationship between the host phenotypic response to RSV infection in the first 6 months of life and the risk of recurrent wheeze and asthma, and b) identify the host genetic and immune response determinants of the RSV infection phenotype that affect the development of early childhood wheezing and asthma following RSV infection. In Project 2, we will focus on the contribution of specific RSV strains to early childhood wheezing and asthma development. RSV strains isolated from the ReSPIRA cohort will be genotyped and clinical parameters such as bronchiolitis severity score, as well as mediators of the host immune response measured in respiratory secretions will be studied to determine how RSV genotypes impact the host response. In Project 3, we will utilize a mouse model of RSV infection to examine the role of the prostaglandin 12 (PGI2) on airway dysfunction of an RSV strain (01/2-20) that has been associated with severe infant bronchiolitis and which induces airway pathology in the mouse. We previously reported that PG12 and signaling through its receptor (IP) is a critical determinant of severity of illness in RSV strain A2 infection. This project will determine the role of host PGI2 in RSV airway pathogenesis and also determine if a PGI2 analog currently used in the treatment of human disease is a target for RSV bronchiolitis. Further, in Project 3, we will use RSV strains isolated from ReSPIRA in Project 2 to determine the generalizability of PGI2 as a therapeutic target.

Public Health Relevance

PUBLIC HEATH RELEVANCE (provided by applicant): RSV is the leading cause of bronchiolitis and causes >100,000 infant hospitalizations in the US each year. Studies have also revealed that severe RSV infection in infancy is associated with the later development of childhood asthma. This application will examine the effects of both host genetic and immune response determinants, as well as the influence of specific RSV strains, on severity of RSV bronchiolitis and childhood asthma. In addition, we will define the role of a novel therapeutic target, PG12, in RSV pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI095227-03
Application #
8511338
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Davidson, Wendy F
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$2,705,916
Indirect Cost
$843,978
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lee, Yu-Na; Hwang, Hye Suk; Kim, Min-Chul et al. (2015) Recombinant influenza virus expressing a fusion protein neutralizing epitope of respiratory syncytial virus (RSV) confers protection without vaccine-enhanced RSV disease. Antiviral Res 115:8-Jan
Ko, Eun-Ju; Kwon, Young-Man; Lee, Jong Seok et al. (2015) Virus-like nanoparticle and DNA vaccination confers protection against respiratory syncytial virus by modulating innate and adaptive immune cells. Nanomedicine 11:99-108
Kwon, Young-Man; Hwang, Hye Suk; Lee, Jong Seok et al. (2014) Maternal antibodies by passive immunization with formalin inactivated respiratory syncytial virus confer protection without vaccine-enhanced disease. Antiviral Res 104:1-6
Lee, Sujin; Quan, Fu-Shi; Kwon, Youngman et al. (2014) Additive protection induced by mixed virus-like particles presenting respiratory syncytial virus fusion or attachment glycoproteins. Antiviral Res 111:129-35
Meng, Jia; Lee, Sujin; Hotard, Anne L et al. (2014) Refining the balance of attenuation and immunogenicity of respiratory syncytial virus by targeted codon deoptimization of virulence genes. MBio 5:e01704-14
Meng, Jia; Stobart, Christopher C; Hotard, Anne L et al. (2014) An overview of respiratory syncytial virus. PLoS Pathog 10:e1004016
Wong, Terianne M; Boyapalle, Sandhya; Sampayo, Viviana et al. (2014) Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology. PLoS One 9:e88764
Dulek, Daniel E; Newcomb, Dawn C; Toki, Shinji et al. (2014) STAT4 deficiency fails to induce lung Th2 or Th17 immunity following primary or secondary respiratory syncytial virus (RSV) challenge but enhances the lung RSV-specific CD8+ T cell immune response to secondary challenge. J Virol 88:9655-72
Zhou, Weisong; Goleniewska, Kasia; Zhang, Jian et al. (2014) Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling. J Allergy Clin Immunol 134:698-705.e5
Yan, Dan; Lee, Sujin; Thakkar, Vidhi D et al. (2014) Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors. Proc Natl Acad Sci U S A 111:E3441-9

Showing the most recent 10 out of 25 publications