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：
9789818
负责人：
Brian Todd Edelson
金额：
$ 59.27万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789818
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) 的疾病结果和病理是由免疫反应类型驱动的在宿主体内，但免疫细胞成功控制结核病的分子要求仍然很差特别是，尽管已知活动性结核病患者中 IL-10 的产生上调。拮抗控制结核分枝杆菌 (Mtb) 感染所必需的途径，由于功能丧失研究（即，在 Mtb 感染期间 IL-10 的影响和功能仍然难以捉摸） Il10-/- 小鼠）仅产生了最小的表型我们之前表明转录因子 Bhlhe40。通过分析多发性硬化症小鼠模型中的 T 细胞中的 IL-10 表达。基因表达数据集，我们现在发现 BHLHE40 转录本的存在量明显较低与健康对照和潜伏性结核病患者相比，活动性结核病患者的丰度较高。活动性结核病患者中 BHLHE40 表达的降低促使我们研究其在结核分枝杆菌感染过程中的作用在小鼠中，我们发现 Mtb 感染期间小鼠 Bhlhe40 的缺失导致 Il10 表达更高， Bhlhe40-/- 中观察到的细菌负荷较高，且早期易感感染。小鼠与缺乏 STAT1 或 NF-κB p50 的小鼠中观察到的结果相似，这两者都是转录因子然而，与 STAT1 和 NF-κB 不同，Bhlhe40 在感染过程中的作用是通过一系列详细的机制研究，我们发现 Bhlhe40 是必需的。 Mtb 感染期间直接抑制 T 细胞和 CD11c+ 细胞中 Il10 的表达，以及在 Mtb 感染过程中删除 Il10 Bhlhe40-/- 小鼠逆转了这些小鼠的易感性。我们的初步数据导致了我们的中心研究。假设 Bhlhe40 在 Mtb 感染期间充当基因表达的关键转录调节因子这是有效控制结核分枝杆菌复制所必需的。我们将通过剖析来解决这一假设。 Bhlhe40 调节 IL-10 产生的机制以及它如何影响 Mtb 的易感性。研究首次调查了 Bhlhe40 在传染病和骨髓细胞中的作用，并将此外，还提供了对感染免疫的分子要求的基本见解。对 Bhlhe40 的研究提供了一个独特的机会来阐明不同水平的 IL-10 如何发挥作用影响结核病，这在其他研究中并不明显，以检验我们的假设并改进。根据我们对这些领域的理解，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 对 Mtb 免疫反应的影响，(2) 剖析机制因此，Bhlhe40 调节免疫细胞中的 Il10 表达，并且 (3) 定义免疫反应在存在较高 Il10 表达的情况下，该基因负责 Mtb 感染的易感性。