Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease in infants and a significant cause of mortality in transplant patients and the elderly. Adequate therapy and vaccines are not currently available. Our preliminary data in a murine model of RSV infection strongly suggests that prostacyclin (PGI2) represents an effective novel therapy for severe RSV-induced illness. Mice that constitutively overexpress PGI 2 synthase are significantly protected against RSV-induced weight loss and mortality, and have reduced viral titers compared to nontransgenic littermates. The objective of this application is to define the mechanism by which PGI2 synthase overexpression confers protection against RSV.
The specific aims are to: 1) Define the immunomodulatory effect of signaling through the PGI2 receptor (known as """"""""IP"""""""") on RSV-induced illness. We hypothesize that PGI 2 signaling through IP will protect against illness caused by RSV. To test this hypothesis, we will use mice in which IP has been knocked-out (IPKO), use mice in which the overexpression ofPGI z synthase can be induced, and use PGI 2 analogs in our in vivo system of RSV infection; 2) Determine the effect ofPGI 2 on antigen presenting cell (APC) differentiation and function. We hypothesize that PGI 2 upregulates APC differentiation and function, enhancing the T cell response to RSV infection. To test this hypothesis, we will define the effect ofPGI 2 synthase overexpression on the quantity and activation of APCs in the lung after RSV infection, and also determine the effect ofa PGI z analog on in vitro APC differentiation; and 3) Determine the contribution ofT lymphocytes to theproteetion conferredbyPGI z synthase overexpressioninRSV-inducedillness. We hypothesize thatthepfincipal mechanism by which PGI 2 synthase overexpressing mice are protected against RSV-induced illness is an effect on lymphocytes. To test this hypothesis, we will define the functional T cell subset and memory response to RSV infection in PGI 2 synthase overexpressing and wild type mice. The proposed studies will define the mechanism by which PGI 2 modulates the immune response to RSV infection and protects against RSV-induced disease.
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