Prostacyclin (PG12) Regulation of RSV-induced Illness

描述(申请人提供)：呼吸道合胞病毒(RSV)是婴儿严重下呼吸道疾病的最重要原因，也是移植患者和老年人死亡的重要原因。目前还没有足够的治疗方法和疫苗。我们在RSV感染小鼠模型中的初步数据有力地表明，前列环素(PGI2)是治疗RSV引起的严重疾病的一种有效的新疗法。与非转基因小鼠相比，结构性过表达PGI2合成酶的小鼠显著防止RSV诱导的体重减轻和死亡，并降低了病毒滴度。本申请的目的是确定PGI2合酶过表达提供对RSV的保护的机制。其具体目的是：1)确定通过PGI2受体(称为“IP”)的信号在RSV诱导的疾病中的免疫调节作用。我们推测，通过IP途径传递的PGI2信号对RSV引起的疾病具有保护作用。为了验证这一假设，我们将使用IP已被敲除的小鼠(IPKO)，使用可诱导PGIz合酶过度表达的小鼠，并在我们的RSV感染体内系统中使用PGI2类似物；2)确定PGI2对抗原提呈细胞(APC)分化和功能的影响。我们推测PGI2上调APC的分化和功能，增强T细胞对RSV感染的反应。为了验证这一假设，我们将确定在RSV感染后，PGI2合酶过表达对肺内APC数量和激活的影响，以及PGIz类似物对体外APC分化的影响；以及3)在RSV诱导的疾病中，T淋巴细胞对PGIz合酶过表达所产生的蛋白的贡献。我们推测，过表达PGI2合酶的小鼠免受RSV诱导的疾病的主要机制是对淋巴细胞的影响。为了验证这一假设，我们将在PGI2合酶过度表达和野生型小鼠中定义功能性T细胞亚群和对RSV感染的记忆反应。拟议的研究将确定PGI2调节RSV感染的免疫反应和预防RSV诱导的疾病的机制。

DESCRIPTION (provided by applicant): 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.