Systems Genetics of Tuberculosis

结核病系统遗传学

• 批准号: 10219083
• 负责人: CHRISTOPHER M SASSETTI
• 金额: $ 216.67万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219083
• 关键词: Address; Affect; Animals; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Biological; Biological Factors; Biological Models; Characteristics; Clinical; Clinical Trials; Collaborations; Complex; Disease; Disease susceptibility; Environmental Risk Factor; Evolution; Failure; Genes; Genetic; Genetic Variation; Genetic study; Genome; Goals; Human; Human Genetics; Immune; Immunologics; Inbred Mouse; Individual; Infection; Intervention; Location; Mammalian Genetics; Modeling; Mus; Mycobacterium tuberculosis; Orthologous Gene; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Population; Population Genetics; Population Heterogeneity; Predisposition; Research; Resolution; Risk; Role; System; Translating; Treatment Efficacy; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccines; Variant; Virulence; bacterial genetics; chemotherapy; co-infection; cohort; combinatorial; design; effective intervention; genetic approach; genetic resource; genetic variant; in vivo; insight; mouse genetics; non-genetic; nutrition; pathogen; preference; programs; tool; trait; vaccination strategy; vaccine efficacy

Systems Genetics of Tuberculosis: Program Abstract: Mycobacterium tuberculosis (Mtb) infection outcomes are highly variable, creating a great challenge in TB control; how do we identify those that are genuinely at risk and deliver an intervention that will be effective for that individual? The biological determinants of Mtb infection outcome have been difficult to define largely because multiple variables are involved, which include genetic variation in host and pathogen and non-genetic environmental factors. To overcome this complexity, we leveraged new mammalian and bacterial genetic resources to create a model system that can be used to study the effect of each of these variables in isolation and in combination. Host diversity is incorporated using mice from the “Collaborative Cross” (CC), a newly generated reference panel of inbred mice that reflects the diversity of an outbred population. Bacterial variation is incorporated using large panels of Mtb strains that reflect both naturally- and experimentally-generated diversity. Using this highly-tractable system, the effect of controlled interventions can be assessed, and high-resolution phenotyping can be applied to differentiate different TB-related disease states. Three inter-related scientific projects will use this uniquely tractable experimental system to: 1) Define host determinants of TB susceptibility, 2) Identify bacterial determinants of host-pathogen preference. 3) Investigate the basis for TB vaccine efficacy in genetically-diverse populations Through collaboration with two essential Scientific Cores focused on Mouse and Human genetics and one Administrative Core, we will accomplish our ultimate scientific goals: to characterize the mechanisms underlying tuberculosis pathogenesis, extend these observations to human clinical cohorts, and use these insights to rationally-design more effective vaccines. !

结核病的系统遗传学：程序摘要： 结核分枝杆菌（MTB）感染结果高度可变，形成了一个 结核病控制中的巨大挑战；我们如何确定那些真正有风险的人以及 提供对该人有效的干预措施？生物学 MTB感染结果的决定因素很难定义很大程度上是因为 涉及多个变量，其中包括宿主和病原体中的遗传变异以及 非遗传环境因素。为了克服这种复杂性，我们利用了新的 哺乳动物和细菌遗传资源以创建可以使用的模型系统 研究每个变量中的每个变量的效果。主持人 使用“协作十字架”（CC）的小鼠（新的）纳入了多样性 产生的近交小鼠的参考面板，反映了杂种的多样性 人口。使用大型MTB菌株掺入细菌变化 反映自然和实验生成的多样性。使用这种高度牵引 系统，可以评估受控干预措施的效果以及高分辨率 表型可用于区分不同的TB相关疾病状态。三 相互关联的科学项目将使用这种独特的实验系统来： 1）定义宿主确定结核病敏感性， 2）确定宿主 - 病原体偏爱的细菌决定剂。 3）研究基因多样性人群中结核病疫苗效率的基础 通过与两个针对鼠标和人类的基本科学核心的合作 遗传学和一个行政核心，我们将实现最终的科学目标： 表征结核病发病机理的机制，扩展这些机制 对人类临床队列的观察，并使用这些见解来合理设计 有效的疫苗。 呢

项目成果

The Phagocyte Oxidase Controls Tolerance to Mycobacterium tuberculosis Infection.

• DOI: 10.4049/jimmunol.1800202
• 发表时间: 2018-09-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Olive AJ;Smith CM;Kiritsy MC;Sassetti CM
• 通讯作者: Sassetti CM

Modeling Diversity: Do Homogeneous Laboratory Strains Limit Discovery?

• DOI: 10.1016/j.tim.2018.08.002
• 发表时间: 2018-11
• 期刊: Trends in microbiology
• 影响因子: 15.9
• 作者: Smith CM;Sassetti CM
• 通讯作者: Sassetti CM

A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response.

结核分枝杆菌 esxH 基因中的天然多态性会破坏 TB10.4 特异性 CD8 T 细胞反应的免疫支配作用。

• DOI: 10.1371/journal.ppat.1009000
• 发表时间: 2020-10
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Sutiwisesak R;Hicks ND;Boyce S;Murphy KC;Papavinasasundaram K;Carpenter SM;Boucau J;Joshi N;Le Gall S;Fortune SM;Sassetti CM;Behar SM
• 通讯作者: Behar SM

Multiplexed Strain Phenotyping Defines Consequences of Genetic Diversity in Mycobacterium tuberculosis for Infection and Vaccination Outcomes.

• DOI: 10.1128/msystems.00110-22
• 发表时间: 2022-06-28
• 期刊: mSystems
• 影响因子: 6.4

Granulocytes act as a niche for Mycobacterium tuberculosis growth.

• DOI: 10.1038/s41385-020-0300-z
• 发表时间: 2021-01
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Lovewell RR;Baer CE;Mishra BB;Smith CM;Sassetti CM
• 通讯作者: Sassetti CM