Exogenous Carbohydrates are Required for Survival for M. tuberculosis

结核分枝杆菌的生存需要外源碳水化合物

• 批准号: 8490492
• 负责人: Jarukit Edward Long
• 金额: $ 5.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490492
• 关键词: Acute; Bacteria; Carbohydrates; Carbon; Cessation of life; Cholesterol; Chronic; Chronic Phase; Data; Disease; Drug Delivery Systems; Environment; Genetic; Growth; Hexose Transporter; Hexoses; Immune response; In Vitro; Infection; Maps; Measures; Membrane; Metabolism; Modeling; Mus; Mutate; Mycobacterium tuberculosis; Nutrient; Organism; Pathway interactions; Phagosomes; Phase; Phosphotransferases; Source; Staging; Sterols; System; Testing; Virulence; base; high throughput screening; in vivo; insight; macrophage; mutant; new therapeutic target; pathogen; success; sugar; uptake

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is responsible for about two million deaths worldwide each year with approximately ten million new cases annually. Like several other intracellular pathogens, the preferred niche for this organism throughout most of the infection, is a modified phagosome-like compartment of the host macrophage. While there are clearly advantages to this pathogenic strategy, growth within a host-derived membrane also poses many challenges. Perhaps the most fundamental is the acquisition of nutrients. How Mtb, or any other vacuolar pathogen, obtains nutrients in this niche is unclear. Furthermore, the environment found inside the phagosome is not static, but rather changes as the disease progresses. Infection with Mtb can be divided into at least two distinct stages: the early preimmune/acute phase and the late postimmune/chronic phase. Previously we used a global genetic interaction mapping strategy to characterize a cholesterol uptake system, called "Mce4." This transporter is only required for survival during the chronic stages of infection, suggesting that the nutrients available to the bacterium change as disease progresses. The carbon source(s) used in the acute phase remains unclear. Using a high-throughput screen for transposon mutants that are defective for growth in acute infection, we have found two putative carbohydrate uptake systems and a hexose kinase that are critical for growth during this phase. The putative sugar importers sugABC, rv2038c-2040c and the hexose kinase ppgK, are important for survival during the early stages of infection suggesting that carbohydrates may serve as important nutrients during this phase. We propose a model in which the adaptive immune response alters the compartment in which Mtb resides, and the bacterium adjusts by shifting from carbohydrate to a cholesterol-based metabolism. To test this hypothesis, we propose to characterize these carbohydrate transporters and hexose kinase, identify the host substrates that serve as nutrients, and identify new therapeutic targets. These studies will provide valuable new drug targets and insight regarding how pathogens adapt in nutrient limited environments inside the host.

描述（由申请人提供）：结核分枝杆菌（Mtb）每年造成全球约200万人死亡，每年约有1000万新发病例。像其他几种细胞内病原体一样，在大多数感染过程中，这种生物体的首选生态位是宿主巨噬细胞的经修饰的吞噬体样区室。虽然这种致病策略有明显的优势，但在宿主来源的膜内生长也带来了许多挑战。也许最基本的是获取营养。结核分枝杆菌或任何其他空泡病原体如何在这个生态位中获得营养尚不清楚。此外，在吞噬体内发现的环境不是静态的，而是随着疾病的进展而变化。Mtb感染可分为至少两个不同的阶段：早期免疫前/急性期和晚期免疫后/慢性期。以前，我们使用了一个全球性的遗传相互作用映射策略来表征胆固醇摄取系统，称为“Mce 4。“这种转运蛋白仅在感染的慢性阶段存活所需，这表明细菌可获得的营养物质随着疾病的进展而变化。急性期使用的碳源仍不清楚。使用高通量筛选转座子突变体是有缺陷的生长在急性感染，我们已经发现了两个假定的碳水化合物摄取系统和己糖激酶，这是关键的增长在这个阶段。假定的糖进口商sugABC，rv 2038 c-2040 c和己糖激酶ppgK，是重要的生存在感染的早期阶段，这表明碳水化合物可能作为重要的营养在这个阶段。我们提出了一个模型，在该模型中，适应性免疫反应改变了结核分枝杆菌所在的隔间，细菌通过从碳水化合物转移到基于胆固醇的代谢来进行调整。为了验证这一假设，我们建议表征这些碳水化合物转运蛋白和己糖激酶，确定作为营养物质的宿主底物，并确定新的治疗靶点。这些研究将提供有价值的新药靶点，并深入了解病原体如何适应宿主内营养有限的环境。