Viral bronchiolitis, secondary to RSV, is often associated with initial wheezing episodes in infancy. In many infants, these episodes precede the onset of asthma. However, neither the pathogenesis of these virus-induced episodes nor a relationship to allergic inflammation and asthma have been well defined. To understand how viral respiratory tract infections influence allergic sensitization, airway inflammation and the development of altered airway function, a murine model to define such interactions has been developed. In this model, mice exposed to live (not inactivated) RSV develop airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) and prior RSV infection enhances the response to subsequent allergen exposure. The responses to RSV and allergen are characterized by eosinophilic inflammation and a requirement for eosinophils in the development of AHR to virus or allergen has been demonstrated. In the current proposal, these observations will be used to define the role of T cells in the development of pulmonary inflammation and AHR following acute RSV infection and in post-viral airway sensitization to allergen. Utilizing T-cell depletion and adoptive transfer of specific T-cell populations, the role of CD4 and CD8 T cells in mediating these responses will be delineated. The importance of Th-1 and Th-2 cytokines in the development of these responses will be examined by targeting specific cytokines and chemokines immunologically and with gene-deficient animals. In these experiments, the regulation and importance of eosinophilic inflammation at different phases of the response will be identified. We will define the role of IL-4 and IgE in response to acute RSV or post-virus exposure to allergen, determining if """"""""atopy"""""""" influences the severity of these responses. These studies provide the foundation for defining the mechanism by which RSV alters airway responsiveness, examining neural control of airway function, particularly targeting cholinergic contractile responsiveness. Mechanisms that alter airway function will also be addressed as a function of the age at which the airway insult (RSV infection + allergen exposure) occurs. To accomplish these goals, we will utilize immunologically- and genetically-manipulated strains of mice as well as the ability to monitor airway function to inhaled MCh over time by whole body plethysmography. This proposal provides a novel approach combining immunologic and physiologic techniques to define how the inflammatory response to RSV contributes to the development of allergen-driven AHR and reveal strategies to prevent the consequences of RSV infection.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Biology and Pathology Study Section (LBPA)
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National Jewish Health
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Jia, Yi; Domenico, Joanne; Takeda, Katsuyuki et al. (2013) Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+ T cell skewing in allergic lung disease. Proc Natl Acad Sci U S A 110:8152-7
Jia, Yi; Takeda, Katsuyuki; Han, Junyan et al. (2013) Stepwise epigenetic and phenotypic alterations poise CD8+ T cells to mediate airway hyperresponsiveness and inflammation. J Immunol 190:4056-65
Okamoto, Masakazu; Takeda, Katsuyuki; Lucas, Joseph J et al. (2012) Low-dose lipopolysaccharide affects lung allergic responses by regulating Jagged1 expression on antigen-pulsed dendritic cells. Int Arch Allergy Immunol 157:65-72
Gelfand, Erwin W (2012) Development of asthma is determined by the age-dependent host response to respiratory virus infection: therapeutic implications. Curr Opin Immunol 24:713-9
Han, Junyan; Dakhama, Azzeddine; Jia, Yi et al. (2012) Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. J Allergy Clin Immunol 130:1175-1186.e9
Takeda, Katsuyuki; Thurman, Joshua M; Tomlinson, Stephen et al. (2012) The critical role of complement alternative pathway regulator factor H in allergen-induced airway hyperresponsiveness and inflammation. J Immunol 188:661-7
Joetham, Anthony; Ohnishi, Hiroshi; Okamoto, Masakazu et al. (2012) Loss of T regulatory cell suppression following signaling through glucocorticoid-induced tumor necrosis receptor (GITR) is dependent on c-Jun N-terminal kinase activation. J Biol Chem 287:17100-8
Waseda, Koichi; Miyahara, Nobuaki; Kanehiro, Arihiko et al. (2011) Blocking the leukotriene B4 receptor 1 inhibits late-phase airway responses in established disease. Am J Respir Cell Mol Biol 45:851-7
Joetham, Anthony; Okamoto, Masakazu; Takeda, Katsuyuki et al. (2011) CD8 regulates T regulatory cell production of IL-6 and maintains their suppressive phenotype in allergic lung disease. J Immunol 186:113-20
Takeda, K; Shiraishi, Y; Matsubara, S et al. (2010) Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation. Br J Pharmacol 160:1399-407

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