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. !

结核病系统遗传学：项目摘要： 结核分枝杆菌 (Mtb) 感染结果差异很大，因此 结核病控制面临巨大挑战；我们如何识别那些真正处于危险之中的人？ 提供对该个人有效的干预措施？ 结核分枝杆菌感染结果的决定因素一直难以定义，很大程度上是因为 涉及多个变量，其中包括宿主和病原体的遗传变异 为了克服这种复杂性，我们利用了新的方法。 哺乳动物和细菌遗传资源创建可使用的模型系统 单独和组合研究每个变量的影响。 使用来自“协作交叉”（CC）的小鼠来整合多样性，这是一种新的方法 参考生成的近交小鼠小组，反映了远交小鼠的多样性 使用大量 Mtb 菌株纳入细菌变异。 反映自然和实验产生的多样性。 系统，可以评估受控干预的效果，并且高分辨率 表型分析可用于区分不同的结核病相关疾病状态。 相互关联的科学项目将使用这个独特的易于处理的实验系统来： 1) 定义结核病易感性的宿主决定因素， 2) 确定宿主-病原体偏好的细菌决定因素。 3) 研究结核疫苗在遗传多样性人群中功效的基础 通过与专注于小鼠和人类的两个重要科学核心的合作 遗传学和一个行政核心，我们将实现我们的最终科学目标： 描述结核病发病机制的特征，扩展这些 对人类临床队列的观察，并利用这些见解来合理设计更多 有效的疫苗。 ！

项目成果

A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.

来自结核分枝杆菌的萜烯核苷诱导泡沫巨噬细胞中的溶酶体脂质储存。

• 发表时间: 2023-03-15
• 作者: Bedard, Melissa;van der Niet, Sanne;Bernard, Elliott M;Babunovic, Gregory;Cheng, Tan;Aylan, Beren;Grootemaat, Anita E;Raman, Sahadevan;Botella, Laure;Ishikawa, Eri;O'Sullivan, Mary P;O'Leary, Seónadh;Mayfield, Jacob A;Buter, Jeffrey;Minn
• 通讯作者: Minn

Heterogeneity in lung macrophage control of Mycobacterium tuberculosis is determined by T cells.

肺巨噬细胞控制结核分枝杆菌的异质性是由 T 细胞决定的。

• 发表时间: 2023-12-01
• 作者: Lai, Rocky;Williams, Travis;Rakib, Tasfia;Lee, Jinhee;Behar, Samuel M
• 通讯作者: Behar, Samuel M

Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.

多个基因位点影响疫苗诱导的针对遗传多样性小鼠中结核分枝杆菌的保护。

• 发表时间: 2024-03
• 影响因子: 6.7
• 作者: Kurtz, Sherry L;Baker, Richard E;Boehm, Frederick J;Lehman, Chelsea C;Mittereder, Lara R;Khan, Hamda;Rossi, Amy P;Gatti, Daniel M;Beamer, Gillian;Sassetti, Christopher M;Elkins, Karen L
• 通讯作者: Elkins, Karen L

Statistical analysis of variability in TnSeq data across conditions using zero-inflated negative binomial regression.

使用零膨胀负二项式回归对不同条件下 TnSeq 数据的变异性进行统计分析。

• 发表时间: 2019-11-21
• 影响因子: 3
• 作者: Subramaniyam, Siddharth;DeJesus, Michael A;Zaveri, Anisha;Smith, Clare M;Baker, Richard E;Ehrt, Sabine;Schnappinger, Dirk;Sassetti, Christopher M;Ioerger, Thomas R
• 通讯作者: Ioerger, Thomas R

Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis.

基因编码的转录可塑性是结核分枝杆菌应激适应的基础。

• 发表时间: 2023-08-20
• 作者: Bei, Cheng;Zhu, Junhao;Culviner, Peter H;Rubin, Eric J;Fortune, Sarah M;Gao, Qian;Liu, Qingyun
• 通讯作者: Liu, Qingyun