Prostacyclin (PG12) Regulation of RSV-induced Illness

描述（由申请方提供）：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（PGI 2）是一种有效的治疗严重RSV诱导疾病的新方法。组成型过表达PGI 2合酶的小鼠显著保护免于RSV诱导的体重减轻和死亡，并且与非转基因同窝出生的小鼠相比具有降低的病毒滴度。本申请的目的是确定PGI 2合酶过表达赋予针对RSV的保护的机制。具体目的是：1）确定通过PGI 2受体（称为“IP”）的信号传导对RSV诱导的疾病的免疫调节作用。我们假设PGI 2通过IP信号传导将防止RSV引起的疾病。为了验证这一假设，我们将使用IP已被敲除（IPKO）的小鼠，使用可以诱导PGI 2合酶过表达的小鼠，并在我们的RSV感染的体内系统中使用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分化和功能，增强T细胞对RSV感染的应答。为了验证这一假设，我们将确定PGI 2合成酶过表达对RSV感染后肺中APC数量和活化的影响，并确定PGI z类似物对体外APC分化的影响; 3）确定T淋巴细胞对RSV诱导的RSV诱导的PGI z合成酶过表达所赋予的保护作用的贡献。我们推测PGI 2合酶过表达小鼠抵抗RSV诱导的疾病的pfinNR机制是对淋巴细胞的影响。为了验证这一假设，我们将确定功能性T细胞亚群和记忆反应RSV感染PGI 2合酶过表达和野生型小鼠。拟议的研究将确定PGI 2调节对RSV感染的免疫应答并保护免受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.