Alveolar type II cell innate immune response to influenza

肺泡 II 型细胞对流感的先天免疫反应

• 批准号: 7787530
• 负责人: ROBERT James MASON
• 金额: $ 43.84万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787530
• 关键词: Alveolar; Antiviral Agents; Apoptotic; Avian Influenza; Bacterial Infections; CXCL10 gene; CXCL11 gene; Cell Communication; Cells; Cigarette Smoker; Collaborations; Dose; Elderly; Epithelial; Epithelial Cells; Floods; Future; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Healed; Human; Immune response; Infection; Inflammatory Response; Inflammatory Response Pathway; Influenza; Influenza A Virus, H1N1 Subtype; Interferons; Interleukin-6; Liquid substance; Na(+)-K(+)-Exchanging ATPase; Pathogenesis; Pathway interactions; Pneumonia; Population; Process; Production; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Regulation; Role; Site; Stem cells; Type II Epithelial Receptor Cell; Viral; Virus; Virus Diseases; alveolar epithelium; alveolar type II cell; cell type; cytokine; healing; insight; macrophage; pandemic influenza; prevent; repaired; response; therapeutic target

DESCRIPTION (provided by applicant): The alveolar epithelium is the site of infection for many emerging viral infections. Alveolar type II cells produce pulmonary surfactant, are the progenitor cells for the type I alveolar epithelial cells, and pump sodium from the alveolar fluid into the interstitium to prevent alveolar flooding. Alveolar epithelial cells also have the ability to initiate both innate and adaptive immune responses. We have shown that human type II cells produce large amounts of IL-29 (interferon ?), a type III interferon, and CXCL10 (IP-10) and CXCL11 (I- TAC), which are important cytokines for initiating the adaptive immune response, as well as a variety of other cytokines in response to influenza. In this application we will determine the regulation of the antiviral interferon response with a focus on IL-29 and the cytokine inflammatory response with a focus on CXCL10, CXCL11, RANTES, and IL-6. We will also determine the role of surfactant protein D (SP-D) in the innate immune response to influenza and its ability to enhance clearance of viral infected apoptotic cells to limit the spread of infection. We believe that SP-D will be very important in alveolar defense against influenza. In addition we will determine if these processes are altered in two susceptible populations, the elderly and current cigarette smokers. Finally we will begin to determine if these responses are regulated by the virus itself by comparing the effects of contemporary circulating viruses to avian influenza and by the presence or absence of the NS-1 gene in the A/PR/8/34 (H1N1) virus. These studies should highlight two new understudied potential therapeutic targets, (i.e., IL-29 and clearance of apoptotic virally infected cells), and provide more insight into the cells that are actually infected in influenza pneumonia. These studies could be easily expanded in the future to other emerging infections after influenza that cause pneumonia or to the pathogenesis of secondary bacterial infections in collaboration with other IMVC awardees.

描述（由申请人提供）：肺泡上皮是许多新出现的病毒感染的感染部位。 II 型肺泡细胞产生肺表面活性物质，是 I 型肺泡上皮细胞的祖细胞，并将钠从肺泡液泵入间质以防止肺泡水淹。肺泡上皮细胞还具有启动先天性和适应性免疫反应的能力。我们已经证明，人类 II 型细胞产生大量的 IL-29（干扰素？）（一种 III 型干扰素）以及 CXCL10 (IP-10) 和 CXCL11 (I-TAC)，它们是启动适应性免疫反应的重要细胞因子，以及响应流感的多种其他细胞因子。在此应用中，我们将确定以 IL-29 为重点的抗病毒干扰素反应的调节，以 CXCL10、CXCL11、RANTES 和 IL-6 为重点的细胞因子炎症反应的调节。我们还将确定表面活性蛋白 D (SP-D) 在流感先天免疫反应中的作用及其增强病毒感染的凋亡细胞的清除以限制感染传播的能力。我们相信 SP-D 在肺泡防御流感方面非常重要。此外，我们将确定这些过程是否在两个易感人群（老年人和当前吸烟者）中发生改变。最后，我们将通过比较当代流行病毒与禽流感的影响以及 A/PR/8/34 (H1N1) 中是否存在 NS-1 基因，开始确定这些反应是否由病毒本身调节。病毒。这些研究应该强调两个新的、尚未研究的潜在治疗靶点（即 IL-29 和凋亡病毒感染细胞的清除），并提供对流感肺炎中实际感染细胞的更多了解。与其他 IMVC 获奖者合作，这些研究将来可以很容易地扩展到流感后引起肺炎的其他新出现的感染，或继发性细菌感染的发病机制。