RSV INDUCED PATTERN OF CYTOKINE EXPRESSION AND DISEASE

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Respiratory Syncytial Virus (RSV) is the most important cause of severe lower respiratory tract disease in infants, rivaling influenza as a cause of excess mortality and morbidity in the elderly, and causing epidemics in bone marrow transplant units with fatality in the majority of cases. Adequate therapy and vaccines are not available, in part because of the unique immunologic features of RSV-induced disease. Formalin-inactivated whole virus vaccine (FI-RSV) did not protect against Infection and was associated with enhanced disease. Data from murine models and evidence from human studies suggest that selective induction of CD4+ T lymphocytes with a Type 2 cytokine expression pattern (dominant IL-4 production) by the FI-RSV vaccine is the basis for vaccine-enhanced illness. Severe RSV bronchiolitis in infants is also associated with Type 2 immune responses. The primary objective of this proposal is to define the mechanisms by which RSV promotes immune responses associated with Type 2 pattern of cytokine production. The specific alms are to: 1) Define the mechanisms by which the RSV G glycoprotein promotes eosinophilia, Th2-like immune responses, and enhanced illness, and 2) Define the mechanisms by which IL-4 delays virus clearance, inhibits CD8+ CTL induction, and promotes enhanced RSV-induced illness. The unique antigenic properties of RSV G will be studied using recombinant vaccinia viruses that express membrane-anchored G, secreted G, or produce both in equal amounts. We will define the role of G structure and antigen processing events on the IL-4 independent induction of IL-5 and eosinophils recently discovered in our laboratory. The mechanism of IL-4 inhibition of CD8+ CTL induction will be defined using recombinant vaccinia viruses constructed in our laboratory that co-express the RSV M2 protein and individual cytokines. The proposed studies will define viral and host factors responsible for patterns of immune response and disease expression after RSV infection. They will improve our basic understanding of how viruses cause disease, and how vaccine-induced immune responses are regulated, will have direct impact on new strategies for development of preventive vaccines and immunotherapeutics for RSV.