Dissecting the genetic basis of protective immunity to tuberculosis in diverse hosts

项目总结 对于长期感染病原体的宿主来说，生存最终取决于一个仔细平衡的宿主。 必须包括抗性和疾病耐受性机制的反应。《抵抗》涉及 直接控制细菌负荷的抗菌途径，而疾病的“耐受性”包括 抵御慢性感染所造成的组织损伤累积损伤的机制。在上下文中 在结核病(TB)中，耐药途径最终被破坏，结核分枝杆菌(Mtb)是 能够在组织中长期坚持。在这一点上，疾病耐受性对于调节免疫反应至关重要。 以防止明目张胆的损害，并确保宿主的最终生存。随着目前治疗方法的失败， 将重点放在直接针对微生物途径上，而不是集中在确定 可用于设计新的以宿主为导向的策略的宿主容忍度。从初步研究到 协作杂交(CC)小组，与标准近交系小鼠不同，我发现CC小组模型 在人类队列中观察到的结核病疾病状态的广泛表型谱。我鉴定了CC基因型别 控制CC小鼠的一系列表型，这些表型具有抵抗力并能够控制细菌负荷， 对于高度易感并在感染后一个月内死于疾病的CC小鼠。虽然我发现了很多 疾病特征通常是相关的，我还发现CC菌株在质量上具有不同的疾病状态， 包括几种典型疾病指标被打破的“异常值”基因类型。例如，细菌负担 在标准的C57BL/6J感染模型中与体重减轻相关，但在携带 107个CFU，我确定了体重减轻和存活率有很大差异的基因类型。几个 其他CC基因型表现出有限的病理变化，并能耐受高负荷的疾病 体重减轻，并在同一CFU死于疾病。这些数据表明，不同的基因 机制是疾病耐受性的基础。在新创新者奖中，该项目将利用这些CC “异常值”菌株作为新的疾病耐受性模型来定义免疫学、细菌和宿主基因 对病原体的保护性免疫的这一基本且未被充分研究的组成部分的机制。 总体而言，这项工作将为与遗传多样性宿主相关的疾病耐受性提供新的见解。 了解疾病耐受性的免疫和遗传介体将允许合理设计 可应用于结核病和其他慢性感染的新的宿主导向策略。

PROJECT SUMMARY For hosts chronically infected with a pathogen, survival is ultimately determined by a carefully balanced host response that must include both resistance and disease tolerance mechanisms. “Resistance” involves antimicrobial pathways that directly control bacterial burden, while disease “tolerance” is comprised of mechanisms to withstand the cumulative damage of tissue damage that chronic infection entails. In the context of tuberculosis (TB), resistance pathways eventually break down, and Mycobacterium tuberculosis (Mtb) is able to persist in tissues long-term. At that point, disease tolerance is vital for regulating the immune response to prevent overt damage and ensure ultimate survival of the host. With the failure of current therapies that focus on directly targeting microbial pathways, this proposal instead focuses on identifying the mediators of host tolerance that may be leveraged to design new host-directed strategies. From preliminary studies through the Collaborative Cross (CC) panel, unlike standard inbred mouse strains, I found that the CC panel models the broad phenotypic spectrum of TB disease states observed in human cohorts. I identified CC genotypes that control a spectrum of phenotypes ranging from CC mice that are resistant and able to control bacterial burden, to CC mice that are highly susceptible and succumb to disease within a month of infection. While I found many disease traits were generally correlated, I also found CC strains harboring qualitatively distinct disease states, including several “outlier” genotypes where typical disease metrics were broken. For example, bacterial burden and weight loss are correlated in the standard C57BL/6J model of infection, yet among CC strains harboring 107 CFU in their lungs, I identified genotypes with a wide variation in weight loss and survival. Several genotypes showed limited pathology and could tolerate disease at high burden, while other CC genotypes exhibited weight loss and succumbed to disease at the same CFU. These data suggest that distinct genetic mechanisms underlie disease tolerance. In the New Innovator Award, this project will leverage these CC “outlier” strains as new models of disease tolerance to define the immunological, bacterial and host genetic mechanisms underpinning this essential and understudied component of protective immunity to pathogens. Overall, this work will provide new insights into disease tolerance that are relevant to genetically diverse hosts. Understanding the immunological and genetic mediators of disease tolerance will allow the rational design of novel host-directed strategies that may be applied to tuberculosis and other chronic infections.