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.

项目概要 对于长期感染病原体的宿主来说，生存最终取决于宿主的仔细平衡 必须包括抵抗和疾病耐受机制的反应涉及“抵抗”。 直接控制细菌负荷的抗菌途径，而疾病“耐受性”包括 抵御慢性感染引起的组织损伤累积损伤的机制。 结核病 (TB) 的耐药途径最终被破坏，结核分枝杆菌 (Mtb) 能够长期存在于组织中，此时，疾病耐受性对于调节免疫反应至关重要。 以防止明显的损害并确保宿主的最终生存。 该提案侧重于直接针对微生物途径，而侧重于确定微生物途径的介体 从初步研究到宿主耐受性，可用于设计新的宿主导向策略。 协作交叉 (CC) 面板，与标准近交小鼠品系不同，我发现 CC 面板模型 通过在人类群体中观察到的结核病状态的广泛表型谱，我确定了 CC 基因型。 控制一系列表型，包括具有抗性并能够控制细菌负荷的 CC 小鼠， 对于高度易感的 CC 小鼠来说，它们会在感染后一个月内死于疾病，而我发现了很多。 疾病特征通常是相关的，我还发现 CC 菌株具有性质不同的疾病状态， 包括一些典型疾病指标被破坏的“异常”基因型，例如细菌负担。 在标准 C57BL/6J 感染模型中，体重减轻与体重减轻相关，但在携带病毒的 CC 菌株中 他们的肺部有 107 个 CFU，我发现了几种在体重减轻和生存方面存在很大差异的基因型。 基因型表现出有限的病理学并且可以耐受高负荷的疾病，而其他 CC 基因型 显示相同 CFU 的体重减轻和死于疾病这些数据表明不同的遗传。 在新创新者奖中，该项目将利用这些 CC 机制。 “异常”菌株作为新的疾病耐受模型来定义免疫学、细菌和宿主遗传 支撑病原体保护性免疫这一重要且尚未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质将有助于合理设计 可应用于结核病和其他慢性感染的新型宿主导向策略。