Prostacyclin (PGI2) Regulation of RSV-induced Illness

描述（由申请人提供）：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。目前还没有适当的治疗和疫苗。我们在RSV感染小鼠模型中的初步数据强烈表明，前列环素（PGI2）是一种有效的治疗严重RSV诱导疾病的新方法。组成性过表达PGI - 2合成酶的小鼠明显免受rsv诱导的体重减轻和死亡率的影响，并且与非转基因小鼠相比，病毒滴度降低。本应用的目的是确定PGI2合成酶过表达对RSV具有保护作用的机制。具体目的是：1)明确通过PGI2受体（称为“IP”）信号传导对rsv诱导疾病的免疫调节作用。我们假设PGI - 2通过IP信号传导可以预防RSV引起的疾病。为了验证这一假设，我们将使用IP被敲除（IPKO）的小鼠，使用可以诱导PGI z合成酶过表达的小鼠，并在我们的RSV感染体内系统中使用PGI 2类似物；2)确定pgi 2对抗原呈递细胞（APC）分化和功能的影响。我们假设PGI 2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PGI 2合成酶过表达对RSV感染后肺部APC数量和激活的影响，并确定PGI z类似物对体外APC分化的影响；3)确定ofT淋巴细胞在rsv诱导的疾病中ypgi z合成酶过表达所赋予的保护作用。我们假设PGI 2合成酶过表达小鼠免受rsv诱导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PGI 2合成酶过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PGI 2调节对RSV感染的免疫反应并保护免受RSV诱导疾病的机制。

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.