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.

项目总结