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

剖析不同宿主对结核病的保护性免疫的遗传基础

• 批准号: 10245989
• 负责人: Clare Margaret Smith
• 金额: $ 144.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245989
• 关键词: Award; Body Weight decreased; Chromosome Mapping; Chronic; Data; Disease; Disease model; Ensure; Exhibits; Failure; Genetic; Genetic Variation; Genotype; Human; Immune response; Immunity; Immunologics; Inbred Strains Mice; Infection; Lung; Mediator of activation protein; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Pathology; Pathway interactions; Phenotype; Reporter; Reproducibility; Resistance; Tissues; Tuberculosis; Variant; Work; antimicrobial; chronic infection; cohort; design; innovation; insight; microbial; mouse model; novel; pathogen; prevent; trait; tuberculosis immunity

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.

项目摘要 对于长期感染病原体的宿主，生存最终由精心平衡的宿主确定 必须包括抗药性和疾病耐受机制的反应。 “抵抗”涉及 直接控制细菌燃烧的抗菌途径，而疾病的“耐受性”已完成 慢性感染实体的组织损害累积损害的机制。在上下文中 结核病（TB），阻力途径最终分解，结核分枝杆菌（MTB）为 它可以长期持续在组织中。那时，疾病耐受性对于控制免疫反应至关重要 防止明显的损害并确保宿主的最终生存。随着当前疗法的失败 专注于直接靶向微生物途径，该提案专注于确定介体 可能利用的宿主容忍度设计新的主机导向策略。从初步研究到 与标准的近交小鼠菌株不同，协作十字架（CC）面板，我发现CC面板模型 在人类人群中观察到的结核病疾病状态的广泛表型谱。我确定了CC基因型 控制一系列表型，这些表型范围从耐药性并能够控制伯嫩细菌的CC小鼠， 对于高度敏感并在感染的一个月内屈服于疾病的CC小鼠。当我找到了很多 疾病特征通常是相关的，我还发现CC菌株具有质量不同的疾病状态， 包括几种“离群”基因型，其中典型疾病指标被打破。例如，细菌伯嫩 在标准的C57BL/6J感染模型中，体重减轻相关，但在携带的CC菌株中 107 CFU在他们的肺中，我发现了体重减轻和存活率较大的基因型。一些 基因型显示有限的病理学，可以忍受高燃烧时疾病，而其他CC基因型 暴露的体重减轻并在同一CFU上屈服于疾病。这些数据表明独特的通用 疾病耐受性的机制。在新的创新奖中，该项目将利用这些CC “异常”菌株作为疾病耐受性的新模型，以定义免疫，细菌和宿主遗传 这是对病原体免疫的基本和理解的组成部分的基础的机制。 总体而言，这项工作将为与一般不同宿主有关的疾病耐受性提供新的见解。 了解疾病耐受性的免疫学和遗传介体将允许合理设计 可以应用于结核病和其他慢性感染的新型宿主指导策略。