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）。更好地了解主机 需要研究影响结核病感染和结核病严重程度的因素，以改进结核病治疗和疫苗。 多方面的证据表明，过度炎症是M。结核病（Mtb） 感染Mtb感染后，巨噬细胞和树突状细胞启动免疫应答，导致 分枝杆菌杀灭、肉芽肿形成和T细胞活化。Toll相互作用蛋白（TOLLIP） 通过抑制几种先天免疫途径，包括TLR和IL-1，介导对Mtb的免疫应答 信号通路我们的长期目标是确定影响细胞凋亡的分子和细胞机制。 疫苗免疫和对结核病的易感性。先天免疫因子的发现，包括TOLLIP， 影响疫苗开发可能影响疫苗设计。这项补助金的目的是描述 TOLLIP在慢性TB或BCG背景下影响T记忆分化和持久性中的作用 exposure.核心假设是TOLLIP缺陷-我们发现的一种表型存在于 多个群体--以有害的方式放大了对结核分枝杆菌的先天免疫反应，削弱了结核分枝杆菌- 特异性T细胞反应和增加TB易感性。其基本原理是， 以微妙的方式影响T细胞免疫的因素为合理的疫苗提供了新的途径 设计我们的具体目标将测试以下假设：1）巨噬细胞中的TOLLIP缺陷是由以下原因引起的： TOLLIP转录复合物的改变，并影响细胞内的多种信号通路。 2）TOLLIP缺乏增加DC活化，这导致T细胞分化增加，但 降低疫苗在人体中的有效性，和3）TOLLIP缺乏损害肺特异性免疫， 特别是在敲除中驻留记忆T细胞和耗尽T细胞的形成和持续中， 小鼠这一贡献是重要的，因为它将确定TOLLIP调节先天免疫。 提高宿主对M.结核病;这项建议可能会导致改进的疫苗 Mtb的佐剂和针对宿主的治疗剂。拟议的工作是创新的，因为我们调查了 TOLLIP的功能活性变体在人类中的作用和机制以及与基因敲除的联合收割机 小鼠感染模型，使用新的工具来研究一种未充分研究的关键免疫调节剂。洞察力 免疫调节基因如TOLLIP是有影响力的，因为它们可以提供新的靶点， 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.