Regulation of Immune Responses to Mycobacterium tuberculosis Infection

结核分枝杆菌感染免疫反应的调节

基本信息

批准号：
10465067
负责人：
Brian Todd Edelson
金额：
$ 59.42万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10465067
关键词：
Address Affect Antigen Presentation Area Binding Biological Assay Cells Cessation of life Communicable Diseases Data Data Set Dendritic Cells Disease Disease Outcome Disease Progression EMSA Gene Expression Genetic Transcription ITGAX gene Immune Immune response Immunity Impairment Infection Inflammation Interleukin-10 Investigation Light Lung Mediating Modeling Molecular Multiple Sclerosis Mus Mycobacterium tuberculosis Myeloid Cells Pathogenesis Pathology Pathway interactions Patients Phenotype Predisposition Production Publishing Regulation Regulator Genes Reporter Resistance Role STAT1 gene Series Signal Transduction Site Source T cell response T-Lymphocyte TNFRSF5 gene Testing Th1 Cells Transcript Transcriptional Regulation Tuberculosis adaptive immune response cell type effective therapy epigenetic marker experimental study immunoregulation improved in vivo insight loss of function mouse model novel response trafficking transcription factor

项目摘要

SUMMARY The disease outcome and pathology of tuberculosis (TB) are driven by the type of immune response mounted in the host, yet the molecular requirements for successful control of TB by immune cells remain poorly understood. In particular, although IL-10 production is upregulated in patients with active TB and is known to antagonize pathways that are essential for the control of Mycobacterium tuberculosis (Mtb) infection, the impact and function of IL-10 during Mtb infection has remained elusive because loss of function studies (i.e, in Il10-/- mice) have yielded only minimal phenotypes. We previously showed that the transcription factor Bhlhe40 regulates IL-10 expression in T cells in a mouse model of multiple sclerosis. By analyzing several published gene expression datasets, we have now found that BHLHE40 transcripts are present in significantly lower abundance in patients with active TB as compared to healthy controls and patients with latent TB. This finding of decreased BHLHE40 expression in patients with active TB led us to investigate its role during Mtb infection in mice. We discovered that loss of Bhlhe40 in mice during Mtb infection results in higher Il10 expression, higher bacterial burden, and early susceptibility to infection. The severe phenotypes observed in Bhlhe40-/- mice are similar to those observed in mice lacking STAT1 or NF-κB p50, both of which are transcription factors central to immune regulation. However, unlike STAT1 and NF-κB, a role for Bhlhe40 during infection is completely unknown. Through a series of detailed mechanistic studies, we find that Bhlhe40 is required to directly repress Il10 expression in T cells and CD11c+ cells during Mtb infection, and deletion of Il10 in Bhlhe40-/- mice reverses the susceptibility of these mice. Our preliminary data have led to our central hypothesis that Bhlhe40 functions as a key transcriptional regulator of gene expression during Mtb infection that is required for effective control of Mtb replication. We will begin to address this hypothesis by dissecting the mechanism by which Bhlhe40 regulates IL-10 production and how this impacts susceptibility to Mtb. Our studies are the first to investigate a role for Bhlhe40 in both infectious disease and in myeloid cells, and will provide fundamental insights into the molecular requirements for immunity to infection. In addition, investigations into Bhlhe40 provide a unique opportunity to shed light on how different levels of IL-10 can impact TB disease, something that has not been evident in other studies. To test our hypothesis and improve our understanding in these areas, we will address the following independent aims: (1) Identify how loss of Bhlhe40 in T cells and CD11c+ cells impacts on immune responses to Mtb, (2) Dissect the mechanism whereby Bhlhe40 regulates Il10 expression in immune cells, and (3) Define the immune responses that are responsible for susceptibility to Mtb infection in the presence of higher Il10 expression.

概括结核病（TB）的疾病结果和病理学由安装的免疫增强响应类型驱动在宿主中，免疫细胞成功控制结核病的分子要求仍然很差理解。特别是，尽管有活性结核病患者的IL-10产生已更新，并且已知对抗控制结核分枝杆菌（MTB）感染至关重要的途径 MTB感染期间IL-10的影响和功能仍然难以捉摸，因为失去了功能研究（即，在 IL10 - / - 小鼠仅产生最小的表型。我们先前证明了转录因子BHLHE40 在多发性硬化症的小鼠模型中调节T细胞中IL-10的表达。通过分析几个已发表的基因表达数据集，我们现在发现BHLHE40转录本以显着较低与健康对照组和潜在结核病患者相比，活动性结核病患者的抽象性。这个发现活性结核病患者的BHLHE40表达的改善导致我们研究了其在MTB感染中的作用在老鼠中。我们发现MTB感染期间小鼠中BHLHE40的损失导致IL10表达更高，较高的细菌灼伤和早期感染的敏感性。 Bhlhe40 - / - 观察到的严重表型小鼠与缺乏STAT1或NF-κBp50的小鼠相似，这两者都是转录因子免疫调节的中心。但是，与STAT1和NF-κB不同，在感染过程中BHLHE40的作用是完全未知。通过一系列详细的机械研究，我们发现BHLHE40需要在MTB感染过程中，直接抑制T细胞和CD11C+细胞中的IL10表达，IL10在 Bhlhe40 - / - 小鼠逆转了这些小鼠的敏感性。我们的初步数据导致了我们的中心假设BHLHE40在MTB感染过程中充当基因表达的关键转录调节剂这是有效控制MTB复制所必需的。我们将通过解剖来解决这一假设 BHLHE40调节IL-10产生的机制以及这如何影响对MTB的敏感性。我们的研究是第一个研究BHLHE40在传染病和髓样细胞中的作用的研究，并将提供对免疫感染的分子要求的基本见解。此外，对BHLHE40的投资提供了一个独特的机会，可以阐明不同水平的IL-10可以如何影响结核病疾病，在其他研究中尚未证明这一点。检验我们的假设并改善我们在这些领域的理解，我们将解决以下独立目标：（1）确定如何损失 T细胞和CD11C+细胞中的BHLHE40影响对MTB的免疫反应，（2）剖析机制因此，BHLHE40调节免疫细胞中的IL10表达，（3）定义免疫反应在较高的IL10表达存在下，负责对MTB感染的易感性。