TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility

项目概要/摘要 2016 年，超过 100 万人死于结核病 (TB)。加深了对宿主的了解 需要了解影响结核病感染和结核病严重程度的因素来改进结核病治疗和疫苗。 多项证据表明，过度炎症会使结核分枝杆菌 (Mtb) 的结果恶化 感染。结核分枝杆菌感染后，巨噬细胞和树突状细胞启动免疫反应，导致 杀灭分枝杆菌、肉芽肿形成和 T 细胞激活。 Toll 相互作用蛋白 (TOLLIP) 通过抑制多种先天免疫途径（包括 TLR 和 IL-1）来介导针对 Mtb 的免疫反应 信号通路。我们的长期目标是确定影响的分子和细胞机制 疫苗免疫力和对结核病的易感性。发现先天免疫因子，包括 TOLLIP， 影响疫苗开发可能会影响疫苗设计。这笔赠款的目的是描述 TOLLIP 在影响慢性结核或卡介苗背景下 T 记忆分化和持久性中的作用 曝光。核心假设是 TOLLIP 缺陷——我们发现的一种表型存在于 多个群体——以有害的方式放大对 Mtb 的先天免疫反应，削弱 Mtb—— 特异性 T 细胞反应和增加结核病易感性。基本原理是先天免疫的识别 以细致入微的方式影响 T 细胞免疫的因素为合理疫苗提供了一条新途径 设计。我们的具体目标将检验以下假设：1) 巨噬细胞中 TOLLIP 缺陷的原因是 TOLLIP 转录复合物的改变并影响多个信号通路 巨噬细胞； 2) TOLLIP 缺乏会增加 DC 的激活，从而导致 T 细胞分化增加，但 降低疫苗对人类的有效性，以及 3) TOLLIP 缺乏会损害肺部特异性免疫力， 特别是在常驻记忆 T 细胞和敲除中耗尽的 T 细胞的形成和持久性方面 老鼠。这一贡献意义重大，因为它将确定 TOLLIP 调节先天免疫 反应并提高宿主对结核分枝杆菌的防御；该提议可能会导致疫苗的改进 Mtb 的佐剂和宿主定向疗法。拟议的工作具有创新性，因为我们调查了 TOLLIP 功能活性变体在人类中的机制和作用以及与敲除相结合 小鼠感染模型，使用新颖的工具来研究未被充分研究的关键免疫调节剂。洞察力 像 TOLLIP 这样的免疫调节基因是有影响力的，因为它们可能提供修改免疫调节基因的新靶点。 免疫反应。

Project Summary/Abstract Over one million people died from tuberculosis (TB) in 2016. Improved understanding of the host factors that influence TB infection and TB disease severity is needed to improve TB treatments and vaccines. Multiple lines of evidence show that excess inflammation worsens outcomes from M. tuberculosis (Mtb) infection. After Mtb infection, macrophages and dendritic cells initiate the immune response, leading to mycobacterial killing, granuloma formation, and T cell activation. The Toll-Interacting Protein (TOLLIP) mediates the immune response to Mtb by dampening several innate immune pathways, including TLR and IL-1 signaling pathways. Our long-term goal is to determine the molecular and cellular mechanisms that influence vaccine immunity and susceptibility to TB. Discovery of innate immune factors, including TOLLIP, that influence vaccine development may influence vaccine design. The objective of this grant is to characterize the role of TOLLIP in influencing T memory differentiation and persistence in the context of chronic TB or BCG exposure. The central hypothesis is that TOLLIP deficiency – a phenotype we have discovered exists in multiple population -- amplifies the innate immune response to Mtb in a deleterious fashion, weakening Mtb- specific T cell responses and increasing TB susceptibility. The rationale is that identification of innate immune factors that influence T cell immunity in a nuanced fashion provides a novel path toward rational vaccine design. Our specific aims will test the following hypotheses: 1) TOLLIP deficiency in macrophages is caused by alterations in the TOLLIP transcriptional complex and influences multiple signaling pathways within the macrophage; 2) TOLLIP deficiency increases DC activation, which leads to increased T cell differentiation but reduced vaccine effectiveness in humans, and 3) TOLLIP deficiency impairs lung-specific immunity, particularly in the formation and persistence of resident memory T cells and exhausted T cells in knockout mice. This contribution is significant because it will establish that TOLLIP regulates the innate immune response and improves host defense against M. tuberculosis; this proposal may lead to improved vaccine adjuvants and host-directed therapeutics to Mtb. The proposed work is innovative because we investigate the mechanisms and effects of a functionally active variant of TOLLIP in humans and combine with a knockout mouse model of infection, using novel tools to investigate an understudied, critical immune regulator. Insight into immunoregulatory genes like TOLLIP is impactful because they may offer new targets for modifying the immune response.