Regulation of Immune Responses to Mycobacterium tuberculosis Infection

结核分枝杆菌感染免疫反应的调节

• 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
• 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

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.

总结 结核病（TB）的疾病结果和病理学是由免疫反应类型驱动的， 然而，通过免疫细胞成功控制结核病的分子要求仍然很差 明白特别是，尽管IL-10的产生在活动性TB患者中上调，并且已知其 拮抗对控制结核分枝杆菌（Mtb）感染至关重要的途径， IL-10在Mtb感染期间的影响和功能仍然难以捉摸，因为功能丧失研究（即， IllO-/-小鼠）仅产生最小的表型。我们以前的研究表明，转录因子Bhlhe 40 调节多发性硬化小鼠模型中T细胞中IL-10的表达。通过分析几个出版的 基因表达数据集，我们现在已经发现BHLHE 40转录本存在于显著较低的 与健康对照组和潜伏性结核病患者相比，活动性结核病患者的结核分枝杆菌丰度。这一发现 BHLHE 40在活动性结核病患者中的表达降低使我们研究了它在结核分枝杆菌感染过程中的作用， 对小鼠我们发现在Mtb感染期间小鼠中Bhlhe 40的缺失导致更高的IL 10表达， 更高的细菌负荷和早期感染易感性。在Bhlhe 40-/-中观察到的严重表型 小鼠与缺乏STAT 1或NF-κB p50的小鼠中观察到的相似，这两种因子都是转录因子 是免疫调节的核心然而，与STAT 1和NF-κB不同，Bhlhe 40在感染过程中的作用是 完全未知通过一系列详细的机制研究，我们发现Bhlhe 40需要 在Mtb感染期间直接抑制T细胞和CD 11 c+细胞中的IL 10表达， Bhlhe 40-/-小鼠逆转了这些小鼠的易感性。我们的初步数据导致我们的中心 假设Bhlhe 40在Mtb感染期间作为基因表达的关键转录调节因子起作用 这是有效控制结核分枝杆菌复制所必需的。我们将开始通过剖析 Bhlhe 40调节IL-10产生的机制以及这如何影响对Mtb的易感性。我们 这些研究是第一次调查Bhlhe 40在感染性疾病和骨髓细胞中的作用， 提供了对感染免疫的分子要求的基本见解。此外，本发明还提供了一种方法， 对Bhlhe 40的研究提供了一个独特的机会，以阐明不同水平的IL-10如何 影响结核病，这在其他研究中并不明显。为了验证我们的假设并改进 我们在这些领域的理解，我们将解决以下独立的目标：（1）确定如何损失的 T细胞和CD 11 c+细胞中的Bhlhe 40对抗结核菌免疫应答的影响 其中Bhlhe 40调节免疫细胞中的Il 10表达，和（3）定义免疫应答， 在存在较高的IL 10表达的情况下负责对Mtb感染的易感性。