Tuberculosis Pathogenesis and Drug Response

结核病发病机制和药物反应

• 批准号: 9264398
• 负责人: CHRISTOPHER M SASSETTI
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264398
• 关键词: Acetyl Coenzyme A; Acetylation; Adenylate Cyclase; Affect; Animals; Antibiotic Therapy; Antibiotics; Behavior; Biochemical; Carbon; Cell Death; Cells; Cessation of life; Chemicals; Chronic; Clinical; Cyclic AMP; Disease; Drug resistance; Environment; Enzymes; Event; Funding; Generations; Genes; Genetic; Goals; Growth; Homeostasis; Hypoxia; Immune; Individual; Infection; Link; Lysine; Maintenance; Metabolic; Metabolism; Methods; Modification; Mutation; Mycobacterium tuberculosis; Nature; Oxidation-Reduction; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Population; Process; Proteins; Proteomics; Regulation; Regulatory Pathway; Role; Signal Transduction; Site; Stress; Structure; Transferase; Triglycerides; Tuberculosis; Work; base; drug efficacy; drug sensitivity; effective therapy; enzyme activity; improved; in vitro activity; in vivo; latent infection; metabolomics; microbial; mutant; prevent; programs; public health relevance; response; treatment duration; tuberculosis treatment

DESCRIPTION (provided by applicant): The defining feature of tuberculosis is the long period of clinical latency during which the causative agent, Mycobacterium tuberculosis (Mtb), grows slowly if at all. It is difficult to overstate the importance of this quiescent behavior, as it likly underlies both the chronic nature of the infection and the relative ineffectiveness of antibiotics. Despite the growing recognition that quiescence is a relatively common microbial response to stress, the physiological state of these slowly- or non-replicating cells has remained enigmatic. To investigate the transition to quiescence, we identified both the genes required for the growth arrest and long-term survival of Mtb during stress-induced stasis, and the metabolic alterations that accompany this transition. Based on these complementary studies, we propose a regulatory cascade that senses host-derived stress, slows bacterial growth, and remodels metabolism for long-term stasis. In this project we will combine high-throughput genetic and biochemical methods to define the structure of this regulatory pathway and determine its ultimate role in promoting bacterial persistence and determining drug efficacy in vivo. We will then characterize the metabolic alterations that are required for the adaptation to quiescence and determine which of these are necessary for survival during stasis. Our goal is to devise new strategies to accelerate tuberculosis therapy through the identification and characterization of cellular pathways that are required for maintaining the quiescent state.

描述（由申请人提供）：结核病的定义特征是长时间的临床潜伏期，在此期间病原体结核分枝杆菌（Mtb）生长缓慢（如果有的话）。很难夸大这种静止行为的重要性，因为它可能是感染的慢性性质和抗生素相对无效的基础。 尽管越来越多的人认识到静止是一种相对常见的微生物对压力的反应，但这些缓慢复制或非复制细胞的生理状态仍然是个谜。 为了研究向静止的过渡，我们确定了在应激诱导的停滞期间Mtb生长停滞和长期存活所需的基因，以及伴随这种过渡的代谢改变。基于这些互补的研究，我们提出了一个调节级联，感觉宿主衍生的压力，减缓细菌生长，并重塑长期停滞的代谢。 在这个项目中，我们将结合联合收割机高通量遗传和生化方法来确定这种调节途径的结构，并确定其在促进细菌持久性和确定体内药物疗效的最终作用。然后，我们将描述适应静止所需的代谢变化，并确定其中哪些是停滞期生存所必需的。我们的目标是设计新的策略，通过识别和表征维持静止状态所需的细胞通路来加速结核病治疗。

项目成果

Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis.

• DOI: 10.1128/mbio.02133-16
• 发表时间: 2017-01-17
• 期刊: mBio
• 影响因子: 6.4
• 作者: DeJesus MA;Gerrick ER;Xu W;Park SW;Long JE;Boutte CC;Rubin EJ;Schnappinger D;Ehrt S;Fortune SM;Sassetti CM;Ioerger TR
• 通讯作者: Ioerger TR

New TB treatments hiding in plain sight.

• DOI: 10.15252/emmm.201404815
• 发表时间: 2015-02
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Olive AJ;Sassetti CM
• 通讯作者: Sassetti CM

Statistical analysis of genetic interactions in Tn-Seq data.

• DOI: 10.1093/nar/gkx128
• 发表时间: 2017-06-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: DeJesus MA;Nambi S;Smith CM;Baker RE;Sassetti CM;Ioerger TR
• 通讯作者: Ioerger TR

The normalcy of dormancy: common themes in microbial quiescence.

休眠的常态：微生物静止的常见主题。

• DOI: 10.1016/j.chom.2013.05.012
• 发表时间: 2013-06-12
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Rittershaus ES;Baek SH;Sassetti CM
• 通讯作者: Sassetti CM

xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.

xCT 通过调节抗菌功能和炎症来增加结核病易感性

• DOI: 10.18632/oncotarget.9052
• 发表时间: 2016-05-24
• 期刊: Oncotarget
• 作者: Cai Y;Yang Q;Liao M;Wang H;Zhang C;Nambi S;Wang W;Zhang M;Wu J;Deng G;Deng Q;Liu H;Zhou B;Jin Q;Feng CG;Sassetti CM;Wang F;Chen X
• 通讯作者: Chen X