Respiratory syncytial virus (RSV) is the most common viral cause of severe lower respiratory tract disease in childhood. Severe RSV-induced disease is associated with childhood asthma, and the incidence of asthma in industrialized countries is increasing. Therefore, understanding the molecular and cellular correlates of RSV-and allergen-induced airway dysfunction is important for devising preventive vaccine and immunotherapeutic strategies to influence the pathogenesis of childhood asthma. The objective of this proposal is to define the virologic and immunologic determinants of airway hyperresponsiveness (AHR) induced by RSV infection in the setting of allergen sensitization. In particular, the mechanism of RSV G glycoprotein-induced airway dysfunction will e defined. In addition, the role of selected cytokines and T cell subsets on the induction of AHR in ovalbumin (ova)-sensitized, RSV-infected mice will be defined. Under normal conditions RSV infection induces a Th1- like pattern of cytokine expression. Our preliminary data supports the hypothesis that ova-sensitization produces an immunologic environment that promotes RSV-specific CD4+ Th2 responses to infection which further potentiate ova-specific allergic airway inflammation and AHR. Further, we hypothesize that RSV infection can permanently alter the immune response to aeroallergens through T cell production of factors such as IFN-alpha or IL-15 that influence memory induction in ova-specific """"""""bystander"""""""" T lymphocytes. To test this hypotheses, we will use well characterized murine models of RSV infection and ova sensitization, and measure methacholine-induced AHR in anesthetized, mechanically- ventilated mice by whole body plethysmography. In addition to defining the role of RSV- and ova-induced cytokines and T lymphocytes subsets in mediating protection from or enhancement of AHR, candidate vaccines and immunotherapeutic approaches will be evaluated for their ability to reduce AHR in ova-sensitized mice following RSV challenge.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045512-02
Application #
6163996
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Adams, Ken
Project Start
1999-03-01
Project End
2004-02-29
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$284,229
Indirect Cost
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
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Hashimoto, Koichi; Durbin, Joan E; Zhou, Weisong et al. (2005) Respiratory syncytial virus infection in the absence of STAT 1 results in airway dysfunction, airway mucus, and augmented IL-17 levels. J Allergy Clin Immunol 116:550-7
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Hashimoto, Koichi; Graham, Barney S; Ho, Samuel B et al. (2004) Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5. Am J Respir Crit Care Med 170:306-12
Peebles Jr, R Stokes; Hashimoto, Koichi; Graham, Barney S (2003) The complex relationship between respiratory syncytial virus and allergy in lung disease. Viral Immunol 16:25-34
Peebles Jr, R Stokes; Hashimoto, Koichi; Morrow, Jason D et al. (2002) Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice. Am J Respir Crit Care Med 165:1154-60
Hashimoto, K; Peebles Jr, R S; Sheller, J R et al. (2002) Suppression of airway hyperresponsiveness induced by ovalbumin sensitisation and RSV infection with Y-27632, a Rho kinase inhibitor. Thorax 57:524-7
Peebles Jr, R S; Graham, B S (2001) Viruses, dendritic cells and the lung. Respir Res 2:245-9
Graham, B S; Johnson, T R; Peebles, R S (2000) Immune-mediated disease pathogenesis in respiratory syncytial virus infection. Immunopharmacology 48:237-47
Peebles Jr, R S; Dworski, R; Collins, R D et al. (2000) Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. Am J Respir Crit Care Med 162:676-81

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