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部位。肺泡II型细胞产生肺表面活性物质，是I型肺泡上皮细胞的前体细胞，并将肺泡液中的钠泵入间质以防止肺泡溢液。肺泡上皮细胞还具有启动先天和获得性免疫反应的能力。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)，这是启动适应性免疫反应的重要细胞因子，以及各种其他细胞因子对流感的反应。在本应用中，我们将以IL-29和细胞因子炎症反应为重点，以CXCL10、CXCL11、RANTES和IL-6为重点，确定抗病毒干扰素反应的调节。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，以及它增强清除病毒感染的凋亡细胞以限制感染传播的能力。我们认为SP-D在预防流感的肺泡防御中起着非常重要的作用。此外，我们将确定这些过程是否会在两个易感人群中发生变化，即老年人和目前吸烟的人。最后，我们将开始通过比较当代流行病毒对禽流感的影响以及A/PR/8/34(H1N1)病毒中是否存在NS-1基因来确定这些反应是否由病毒本身调节。这些研究应该突出两个新的未被研究的潜在治疗靶点(即IL-29和清除凋亡的病毒感染细胞)，并为流感肺炎中实际感染的细胞提供更多洞察。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，或者与其他IMVC获奖者合作，研究继发性细菌感染的发病机制。