Childhood allergic asthma has been and still is a growing health problem in the western world. Many children begin to have significant complications from severe asthma due to environmental allergens such as cockroach allergen (CRA) early in life. The clinical manifestations include increased airway hyperreactivity, altered lung function and peribronchial inflammation. In most cases these children develop a chronic pulmonary disorder that results in asthma later in their life. Infection with respiratory syncytial virus (RSV), commonly known as a 'pediatric virus'may be an initiating infection but also exacerbates the pulmonary disease in these children, necessitating hospitalization and frequent recurrent hospital visits adding to the burden of health care costs. RSV also exacerbates disease in susceptible adult populations with existing pulmonary disorders such as asthma and COPD. Thus, viral exacerbation of existing lung diseases remains a serious problem. Previous studies in mice have shown RSV elicits a Th2 inflammatory response with hyper-secretion of mucus and decreased viral clearance causing significant pulmonary pathology. In this proposal RSV exacerbation of an allergen response will be investigated with specific focus on Th2 cytokine associated disease severity. The T cell responses during allergen sensitization or viral infection are dictated by the cytokine environment and through instructive signals from Notch ligand Delta-like 4 (Dll4). The role of Notch in T cell development is well established while its role in peripheral T cell regulation has only begun to be appreciated. Our recent data demonstrated that Dll4 is upregulated on antigen presenting cells following primary RSV infection and results in altered Th2 responses in vivo. Our preliminary studies suggest that Dll4 augments Th2 cytokine production during RSV exacerbation of existing allergic lung disease. This augmented T cell response by Dll4 is due to upregulation of lunatic fringe (LFNG), a glycosyltransferase that enhances Notch receptor activation by ligands belonging to the Delta-like family and inhibits Notch activation by jagged ligands. These preliminary studies provide the rationale for our central hypothesis that increased expression of LFNG in an existing Th2 environment augments Dll4 signaling and enhances Th2 response during viral exacerbation. To further understand the role of LFNG in this disease we propose the following aims - i) identify the specific role of LFNG during viral exacerbation of existing allergic lung disease and ii) determine the molecular mechanisms regulating LFNG in a Th2 environment. Further, we also observed that the expression of notch receptors 1 (N1) and 2 (N2) are specifically increased in T cells under in vitro Th2 conditions that recapitulate an in vivo allergic Th2 environment in mice. Thus our final aim - iii) is to address the regulation of Th2 cytokines by notch receptors in the context of LFNG during viral exacerbation of existing allergic disease.
These studies will provide novel insights into the role of LFNG and Notch in Th2 inflammation and pulmonary pathology during viral exacerbation of existing allergic disease. Further we will identify the molecular mechanisms dictating the expression of lunatic fringe and Notch in T cells during development of Th2 environment. Our long-term goals with our ChIP-seq study using bioinformatics tools will identify putative targets that can be exploited therapeutically for patients suffering from RSV exacerbated disease. Additionally these observations may provide important clinical correlates to other existing allergies and secondary viral infections.
|Mukherjee, Sumanta; Rasky, Andrew J; Lundy, Phil A et al. (2014) STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease. J Immunol 192:996-1003|