TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility

项目摘要/摘要 2016年有100多万人死于结核病。提高了对主机的了解 需要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。 多条证据表明，过度炎症会恶化结核分枝杆菌(结核分枝杆菌)的预后。 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 分枝杆菌杀灭、肉芽肿形成和T细胞激活。Toll相互作用蛋白(TOLLIP) 通过抑制包括TLR和IL-1在内的几种天然免疫途径来介导对结核分枝杆菌的免疫应答 信号通路。我们的长期目标是确定影响 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， 影响疫苗开发可能会影响疫苗设计。这笔赠款的目的是为了描述 TOLLIP在影响慢性结核或卡介苗患者T记忆分化和持久性中的作用 曝光。中心假设是TOLLIP缺乏症--我们发现的一种表型存在于 多种群--以有害的方式放大对结核分枝杆菌的天然免疫反应，削弱结核分枝杆菌-- 特异性T细胞反应和增加结核病易感性。其基本原理是识别先天免疫 以细微差别方式影响T细胞免疫的因素提供了一条通往合理疫苗的新途径 设计。我们的具体目标将检验以下假设：1)巨噬细胞中TOLLIP缺乏是由 TOLLIP转录复合体的改变并影响体内的多个信号通路 巨噬细胞；2)TOLLIP缺乏增加DC激活，从而导致T细胞分化增加，但 降低了疫苗对人类的效力，以及3)TOLLIP缺乏会损害肺部特异性免疫， 尤其是在基因敲除中驻留记忆T细胞和耗尽T细胞的形成和持续 老鼠。这一贡献意义重大，因为它将确立TOLLIP调节先天免疫 应答并提高宿主对结核分枝杆菌的抵抗力；这一建议可能导致改进疫苗 结核分枝杆菌的佐剂和宿主导向疗法。拟议的工作具有创新性，因为我们调查了 TOLLIP功能活性变异体与基因敲除联合作用的机制和作用 小鼠感染模型，使用新工具研究一种未被充分研究的关键免疫调节因子。洞察力 像TOLLIP这样的免疫调节基因是有影响的，因为它们可能为修改 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.