Exogenous PGI2 protection against RSV-induced illness

外源性 PGI2 可以预防 RSV 引起的疾病

• 批准号: 8910077
• 负责人: Melissa H. Bloodworth
• 金额: $ 2.96万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-29 至 2021-01-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910077
• 关键词: Activities of Daily Living; Antibodies; Antiviral Agents; Arachidonic Acids; Attenuated; Body Weight decreased; Bronchiolitis; CD8B1 gene; Cells; Childhood Asthma; Chimeric Proteins; Clinical; Clinical effectiveness; Data; Development; Environmental air flow; Enzymes; Epidemiologic Studies; Epoprostenol; FDA approved; Frequencies; Functional disorder; Genes; Genetic Polymorphism; Histology; Hospitalization; Human; Immune response; Immunity; Infant; Infection; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-13; Laboratories; Lower Respiratory Tract Infection; Lung; Lymphoid Cell; Mediating; Monoclonal Antibodies; Mucous body substance; Mus; Outcome; Palivizumab; Pathway interactions; Prevention; Production; Promoter Regions; Publishing; Pulmonary Edema; Pulmonary Hypertension; Recovery; Regulatory T-Lymphocyte; Reporting; Respiratory Failure; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk Factors; Role; Severities; Signal Transduction; Source; Supportive care; T-Cell Activation; T-Lymphocyte; United States; Vaccines; Viral; Virus Diseases; Western Blotting; airway epithelium; airway obstruction; clinically significant; cost effective; cytokine; hypertension control; improved; infancy; new therapeutic target; overexpression; preclinical study; public health relevance; receptor; research study; therapeutic target; urinary; virus pathogenesis

 DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization, and severe RSV bronchiolitis has been identified as a risk factor for th subsequent development of asthma in children. There is no currently available therapy for RSV bronchiolitis. Moreover, no vaccine is FDA-approved and the only prevention option for RSV infection is palivizumab, a monoclonal antibody directed against the RSV fusion protein. Given the frequency and severity of infection, the development of new treatment options is imperative. Our preliminary data suggest that exogenous prostaglandin (PG) I2 is a novel therapeutic target for RSV. Our group reported that mice that constitutively overexpress PGI synthase (PGIS) were significantly protected from RSV-induced illness. In addition, we found that mice which cannot signal through the PGI2 receptor (IP) had significantly exacerbated weight loss and delayed recovery after RSV infection. In a collaborative study of infants admitted with RSV bronchiolitis, we found that a functional polymorphism in the promoter region of the PGI synthase (PGIS) gene was associated with an increase in the urinary PGI2 metabolite and less severe RSV bronchiolitis. These data strongly support that endogenous PGI2 protects against RSV-induced illness. To pave the way for a clinical effectiveness study using PGI2 for the treatment of RSV infection, we must perform preclinical studies to determine how exogenous PGI2 regulates RSV-induced illness and determine the mechanisms by which exogenous PGI2 modulates host antiviral immunity. Interleukin 13 (IL-13) can be produced by T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s). During RSV infection, IL-13 mediates mucus production, which directly contributes to airway obstruction and respiratory failure. On the other hand, IL-10, which can be produced by T regulatory cells (Tregs), inhibits RSV-induced inflammation. RSV-specific CD8+ T cells are a major source of IFN- , which limits viral replication. I found significantly decreased lung IL-13 accompanied by increased lung IL-10 and IFN- in RSV-infected mice treated with exogenous PGI2. Accordingly, I hypothesize that exogenous PGI2 attenuates IL-13 producing- Th2 cells and ILC2s while enhancing IFN- -producing CD8+ T cells and IL-10-producing Tregs during RSV infection, resulting in decreased RSV-induced illness. In Aim 1, I hypothesize that exogenous PGI2 inhibits RSV-induced Th2 cell and ILC2 cytokine expression and proliferation, while enhancing Treg cytokine expression and proliferation, resulting in attenuated mucus production. In Aim 2, I hypothesize that exogenous PGI2 enhances RSV-specific CD8+ T cell activation and proliferation, resulting in decreased viral replication during RSV infection. These studies will advance the field in that they will determine how PGI2, an FDA-approved agent, attenuates RSV illness. The current availability of PGI2 for human treatment highlights the clinical significance of my studies as this therapy could be immediately transferrable to RSV disease.

 描述（由申请人提供）： 呼吸道合胞病毒 (RSV) 是婴儿住院的主要原因，严重的 RSV 细支气管炎已被确定为儿童随后发生哮喘的危险因素 目前尚无针对 RSV 细支气管炎的治疗方法。此外，FDA 还没有批准任何疫苗，鉴于 RSV 感染的频率和严重程度，帕利珠单抗是一种针对 RSV 融合蛋白的单克隆抗体。感染，开发新的治疗方案势在必行。我们的初步数据表明，外源性前列腺素 (PG) I2 是 RSV 的新治疗靶点。我们的研究小组报告称，持续过度表达 PGI 合酶 (PGIS) 的小鼠可显着免受 RSV 诱导的感染。此外，在一项针对患有 RSV 细支气管炎的婴儿的合作研究中，我们发现无法通过 PGI2 受体 (IP) 发出信号的小鼠在感染 RSV 后体重减轻明显加剧且恢复延迟。发现 PGI 合酶 (PGIS) 基因启动子区域的功能多态性与尿 PGI2 代谢物的增加和 RSV 细支气管炎的减轻有关，这些数据支持内源性 PGI2 可以预防 RSV 诱发的疾病。对于使用 PGI2 治疗 RSV 感染的临床有效性研究，我们必须进行临床前研究，以确定外源性 PGI2 如何调节 RSV 引起的疾病并确定其机制外源性 PGI2 可以通过 T 辅助细胞 2 (Th2) 和第 2 组先天淋巴细胞 (ILC2) 来调节宿主抗病毒免疫。在 RSV 感染过程中，IL-13 可以直接介导粘液产生。另一方面，调节性 T 细胞 (Treg) 产生的 IL-10 会抑制 RSV 引起的炎症。 RSV 特异性 CD8+ T 细胞是 IFN- 的主要来源，它限制了病毒复制，我发现在接受外源性 PGI2 治疗的 RSV 感染小鼠中，肺 IL-13 显着降低，同时肺 IL-10 和 IFN- 增加。其次，在 RSV 感染期间，外源性 PGI2 会减弱产生 IL-13 的 Th2 细胞和 ILC2，同时增强产生 IFN- 的 CD8+ T 细胞和产生 IL-10 的 Tregs，从而导致在目标 1 中，我认为外源性 PGI2 会抑制 RSV 诱导的 Th2 细胞和 ILC2 细胞因子的表达和增殖，同时增强 Treg 细胞因子的表达和增殖，从而导致粘液产生减弱。在目标 2 中，我认为外源性 PGI2 会减弱。增强 RSV 特异性 CD8+ T 细胞的激活和增殖，从而减少 RSV 感染期间的病毒复制。这些研究将推动该领域的发展。 将确定 PGI2（FDA 批准的药物）如何减轻 RSV 疾病 目前 PGI2 用于人类治疗凸显了我的研究的临床意义。 治疗可以立即转移到 RSV 疾病。