Respiratory Syncytial Virus (RSV) is an important human pathogen producing significant morbidity in both infants and the elderly. Two unique features of the host response to RSV are 1). the immune-mediated enhanced lung injury observed in individuals undergoing natural infection after immunization with standard vaccine preparations (inactivated virions), and 2). the susceptibility of RSV-infected individuals to repeat RSV infection. This proposal is designed to investigate the regulation of the CD4+ and CD8+ T cell response in the lungs to experimental RSV infection in the murine model, and the role of specific RSV gene products in modulating the effector activity and memory response of RSV-specific T cells in the lungs. The approach is predicated on several of our recent observations in this model including: the identification of a unique oligoclonal population of memory effector CD4+ T cells in the lungs which orchestrate Th-2 enhanced injury in RSV-G-immune individuals undergoing challenge infection; evidence indicating extensive proliferation of activated specific CD4+ memory T cells in the lungs displaying a deficient effector cytokine response; the demonstration of a selective defect in the effector activity of CD4+ T cells responding to RSV infection in the lungs, and the concomitant rapid decline in the frequency of memory CD8+ T cells selectively in the lungs after RSV infection. Based on these and related observations, we propose the following Specific Aims: 1). To characterize the specificity and the regulation of the effector cytokine profile of RSV-G-specific lung CD4+ T cells; 2). To define the signaling defect in effector activity-deficient lung CD8+ T cells, and to identify specific RSV gene product(s) orchestrating this defect. We will exploit several newer technologies (e.g., MHC class II tetramers, intracellular staining of signaling pathway intermediates) to define the effector cytokine response of CD4( T cells, and the likely signaling defects in lung CD8(T cells; and we will employ conventional approaches (i.e., lung virus titers, MHC class I tetramer staining) to assess memory duration and resistance to challenge infection. Mutant RSV viruses constructed by reverse genetics technology will be employed to identify potential viral gene products regulating effector T cell responses. The study should provide new and useful information -- both for our understanding of RSV pathogenesis and for the development of an effective RSV vaccine.
Showing the most recent 10 out of 32 publications
