Vitamin D and Innate Immunity in Respiratory Infections

维生素 D 和呼吸道感染的先天免疫

• 批准号: 8710744
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 12.61万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710744
• 关键词: Address; Air; Anti-Bacterial Agents; Antibiotics; Binding Sites; Biological Response Modifiers; CCAAT-Enhancer-Binding Proteins; Calcitriol; Cells; Cessation of life; ChIP-seq; Communicable Diseases; DNA; Defensins; Development; Disease; Epithelial Cells; Epithelium; Exploratory/Developmental Grant; Foundations; Gene Expression; Gene Expression Regulation; Genes; Goals; Host Defense; Human; Immune; Immune response; Immunologic Receptors; In Vitro; Infection; Laboratories; Lead; Life; Link; Lipopolysaccharides; Liquid substance; Lung; Mediating; Methods; Modeling; Mucous Membrane; Mus; Myeloid Cells; Natural Immunity; Pathway interactions; Pattern recognition receptor; Peptides; Play; Production; Publishing; Receptor Activation; Regulation; Regulatory Pathway; Research; Respiratory Tract Infections; Risk; Role; Solid; Streptococcus pneumoniae; Structure of respiratory epithelium; Time; Toll-Like Receptor Pathway; Toll-like receptors; Vitamin D; airway epithelium; antimicrobial drug; antimicrobial peptide; base; cathelicidin; cathelicidin antimicrobial peptide; chemokine; cofactor; defense response; genome wide association study; in vivo; innate immune function; microorganism; mouse model; novel; pathogen; promoter; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): The respiratory epithelium is the first line of defense against inspired pathogenic microorganisms. One component of this defense is the production of antimicrobial peptides such as ¿-defensins and cathelicidins. The long-range goal of our research has been to understand host-pathogen interactions in the airway epithelium. Identification of a non-toxic agent that could increase antibacterial capabilities of the airway through transcriptional mechanisms could have long-reaching implications for the treatment of airway infections. Toward this goal, we recently demonstrated that an antimicrobial peptide, the cathelicidin LL-37, can be induced in airway epithelial cells (AEC) grown in an air-liquid interfac (ALI) by the hormonally active form of vitamin D, 1,25(OH)2D3. In addition, we observed the induction of a novel innate immune receptor, Triggering Receptor Expressed on Myeloid cells (TREM-1) on AEC. After TREM-1 levels are increased by 1,25(OH)2D3, activation of this receptor results in stimulation of innate immune mediators, including ¿-defensins. We have further identified transcription factor binding sites in the promoter of these 1,25(OH)2D3-regulated innate immune genes that may be required for the induction. Thus we have uncovered a novel method for innate immune stimulation of airway cells. Based upon these results, we hypothesize that 1,25(OH)2D3 can increase the antibacterial and overall innate immune response of the airway epithelium. However, in order to address this hypothesis, we must first understand the relationship between vitamin D and innate immunity in the airway. Thus, we are proposing here an exploratory study to characterize the effect of vitamin D on innate immune pathways and on in the innate immune defense of the airway. In specific aim 1 we will characterize the cross- talk between the TLR-based innate immune pathways and the vitamin D pathways regulating LL-37 and TREM-1 expression in vitro. In specific aim 2, we will define the mechanism of innate immune regulation of the vitamin D regulatory pathway in airway epithelial cells through a characterization of the pathways and transcription factors leading to LL-37 and TREM-1 gene expression in airway epithelial cells. In specific aim 3 we will determine the effect of 1,25(OH)2D3 on innate immunity in a mouse model of airway infection, using our existing airway infection model of intranasal inoculation of Streptococcus pneumoniae to quantify the effect of 1,25(OH)2D3 on airway host defense in vivo. Since murine cathelicidin is not regulated by vitamin D, we will examine the effect of 1,25(OH)2D3 in vivo using a humanized mouse expressing the human LL-37 gene under the control of its own promoter. The results of our three aims will provide a solid foundation for further in-depth analysis of the roles played by these innate immune mediators in host defense of the airway, and of the potential for the development of 1,25(OH)2D3 treatment as a therapy for airway infections. This application is appropriate for the R21 mechanism because it involves considerable risk but may lead to a breakthrough in vitamin D and innate immunity that could have a major impact on research in the field of airway infections.

描述（由应用提供）：呼吸上皮是针对受启发的致病微生物的第一道防线。该防御的一个组成部分是生产抗菌胡椒体，例如 - 二防御素和cathelicidins。我们研究的远程目标是了解气道上皮中的宿主 - 病原体相互作用。通过转录机制可以鉴定出可能增加气道抗菌能力的无毒剂，可能会对气道感染的治疗具有长期的影响。为了实现这一目标，我们最近证明了可以通过维生素D，1,25（OH）2D3在气道上皮细胞（AEC）中诱导的抗菌肽cathelicidin LL-37（AEC）。此外，我们观察到了一种新型的先天免疫受体的诱导，该受体在AEC上触发了在髓样细胞（TREM-1）上表达的受体。在TREM -1水平增加1,25（OH）2d3之后，该受体的激活导致刺激先天免疫介质，包括`` - fefensin''。我们在这1,25（OH）2d3调节的先天免疫原中，进一步鉴定了转录因子结合位点，这可能是诱导所需的。我们发现了一种新型的气道细胞免疫模拟方法。基于这些结果，我们假设1,25（OH）2d3可以增加气道上皮的抗菌和整体先天免疫反应。但是，为了解决这一假设，我们必须首先了解气道中维生素D与先天免疫组织化学之间的关系。在特定目标1中，我们将表征基于TLR的先天免疫组织化学途径与调节LL-37和TREM-1表达的维生素D途径之间的串扰。在特定的目标2中，我们将通过表征导致气道上皮细胞中LL-37和TREM-1基因表达的途径和转录因子的表征来定义气道上皮细胞中维生素D调节途径的先天免疫调节机制。在特定目的3中，我们将使用现有的气道感染模型在气道感染的小鼠模型中确定1,25（OH）2d3对先天免疫调节的影响，用于肺炎链球菌的鼻内接种模型，以量化1,25（OH）2d3对气道宿主在Vivo中的影响。由于鼠Cathelicin不受维生素D的调节，因此我们将使用在其自身启动子的控制下使用人源化的小鼠来检查1,25（OH）2d3在体内的效果。我们三个目标的结果将为进一步分析对角色的作用提供坚实的基础 这些先天的免疫接种者在托管气道的托管方面，以及开发1,25（OH）2d3治疗的潜力作为气道感染的疗法。该应用适用于R21机制，因为它涉及考虑风险，但可能会导致维生素D和先天免疫组织化学的突破，这可能会对气道感染领域的研究产生重大影响。