Overcoming nutritional immunity: Staphylococcal adaptation to host-imposed manganese and zinc starvation

克服营养免疫：葡萄球菌对宿主造成的锰和锌饥饿的适应

• 批准号: 9176192
• 负责人: Thomas Everett Kehl-Fie
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176192
• 关键词: Abscess; Amino Acids; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Biochemical Genetics; Biochemistry; Biological Assay; Carbon; Catabolism; Cells; Centers for Disease Control and Prevention (U.S.); ChIP-seq; Defect; Development; Disease; Energy-Generating Resources; Engineering; Environment; Enzymes; Genus staphylococcus; Glucose; Glycolysis; Goals; Health; Host Defense; Human; Immune; Immune response; Immunity; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Infection; Invaded; Investigation; Isoenzymes; Lead; Leukocyte L1 Antigen Complex; Manganese; Metabolic Pathway; Metabolism; Metals; Methicillin; Microbe; Microbiology; Mus; Nutrient; Nutritional; Process; Proteins; Publishing; Reagent; Regulation; Reporter; Reporting; Resistance; Series; Signal Transduction; Site; Source; Spectrum Analysis; Staphylococcus aureus; Starvation; Superoxide Dismutase; System; Techniques; Therapeutic Intervention; Vancomycin; Variant; Virulence; Work; World Health Organization; Zinc; abstracting; bacterial genetics; base; burden of illness; cofactor; combat; enzyme activity; experience; genetic approach; innovation; insight; interdisciplinary approach; metabolomics; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; preference; prevent; research study; response; soft drink; sugar; Abscess; Amino Acids; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Biochemical Genetics; Biochemistry; Biological Assay; Carbon; Catabolism; Cells; Centers for Disease Control and Prevention (U.S.); ChIP-seq; Defect; Development; Disease; Energy-Generating Resources; Engineering; Environment; Enzymes; Genus staphylococcus; Glucose; Glycolysis; Goals; Health; Host Defense; Human; Immune; Immune response; Immunity; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Infection; Invaded; Investigation; Isoenzymes; Lead; Leukocyte L1 Antigen Complex; Manganese; Metabolic Pathway; Metabolism; Metals; Methicillin; Microbe; Microbiology; Mus; Nutrient; Nutritional; Process; Proteins; Publishing; Reagent; Regulation; Reporter; Reporting; Resistance; Series; Signal Transduction; Site; Source; Spectrum Analysis; Staphylococcus aureus; Starvation; Superoxide Dismutase; System; Techniques; Therapeutic Intervention; Vancomycin; Variant; Virulence; Work; World Health Organization; Zinc; abstracting; bacterial genetics; base; burden of illness; cofactor; combat; enzyme activity; experience; genetic approach; innovation; insight; interdisciplinary approach; metabolomics; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; preference; prevent; research study; response; soft drink; sugar

Project Summary/Abstract: Bacterial infections are of serious concern to human health because of the continued emergence and spread of antibiotic resistance. Reports by both the Centers for Disease Control and World Health Organization have stated that the end of the antibiotic era is upon us. They also called for the development of new therapeutic strategies for treating bacterial pathogens, such as Staphylococcus aureus. A powerful strategy utilized by the host to combat invading pathogens is the restriction of essential nutrients, such as manganese (Mn) and zinc (Zn). Despite experiencing Mn and Zn starvation during infection, S. aureus and other successful pathogens remain capable of causing disease. Elucidating how bacteria adapt to this host defense has the potential to identify new targets for therapeutic intervention, the disruption of which will enhance the efficacy of the host immune response. Recent work revealed that a critical component of the nutrient withholding response is the Mn- and Zn-binding immune effector protein calprotectin (CP). This finding allowed the creation of novel reagents based on CP that can be used to impose highly specific and biologically relevant metal starvation in culture. Utilizing these reagents revealed that the bacterial two-component signal transduction system ArlRS is a critical regulator of the staphylococcal response to host-imposed metal starvation. Surprisingly, while ArlRS is known to contribute to staphylococcal virulence, the signal that activates the system and the direct vs. indirect targets of the system are unknown. Further investigations suggest that Mn and Zn sequestration prevents S. aureus from utilizing sugars, but not amino acids, as an energy source. This observation suggests that Mn and Zn starvation disrupts glycolysis in S. aureus. Recent work in other species has shown that glycolysis can be dependent on these metals. They also revealed that the expression of two putatively Mn-dependent superoxide dismutases, which is unique to S. aureus, promotes resistance to host- imposed nutrient metal starvation. In total, these results lead to the hypothesis that S. aureus profoundly alters how it generates energy and expresses alternative enzymes in order to adapt to host-imposed Mn and Zn starvation. The Aims of this proposal will evaluate this hypothesis and elucidate how S. aureus adapts to Mn and Zn starvation. Aim I. Elucidate the direct vs. indirect targets of the ArlRS regulatory network and the environmental signals that modulate activity of the system. Aim II. Determine the impact of Mn and Zn starvation on staphylococcal central metabolism and carbon source preference. Aim III. Elucidate how metal availability impacts the contributions of SodA and SodM to staphylococcal disease. To accomplish these aims an interdisciplinary approach utilizing techniques taken from microbiology and biochemistry, as well as advanced elemental quantification and whole cell paramagnetic spectroscopy, will be utilized.

项目摘要/摘要： 由于持续出现和 抗生素耐药性的传播。疾病控制中心和世界卫生组织的报告 已经指出，抗生素时代的终结即将到来。他们还呼吁开发新的 治疗细菌病原体的治疗策略，例如金黄色葡萄球菌。有力的策略 宿主利用来对抗入侵的病原体是必需营养素的限制，例如锰 （MN）和锌（Zn）。尽管在感染期间经历了Mn和Zn饥饿，但金黄色葡萄球菌和其他成功 病原体仍然能够引起疾病。阐明细菌如何适应该宿主防御的 潜力确定治疗干预的新目标，其中断将增强 宿主免疫反应。最近的工作表明，养分预扣的关键组成部分 反应是MN和Zn结合免疫效应蛋白钙染色蛋白（CP）。这一发现允许创造 基于CP的新型试剂，可用于施加高度特异性和与生物学相关的金属 文化中的饥饿。利用这些试剂发现细菌两组分组信号转导 System ARLRS是葡萄球菌反应对宿主施加金属饥饿的关键调节剂。 令人惊讶的是，虽然已知ARLR有助于葡萄球菌毒力，但信号激活了 系统和直接与间接目标的系统尚不清楚。进一步的调查表明MN 和锌固固性可防止金黄色葡萄球菌利用糖，而不是氨基酸作为能源。这 观察表明，Mn和Zn饥饿破坏了金黄色葡萄球菌中的糖酵解。最近在其他物种中的工作 已经表明糖酵解可以取决于这些金属。他们还揭示了两个的表达 金黄色葡萄球菌所独有的推定的Mn依赖性超氧化物歧化酶促进了对宿主的抗性 施加了营养金属饥饿。总的来说，这些结果总共导致了金黄色葡萄球菌深刻改变的假设 它如何产生能量并表达替代酶，以适应宿主施加的Mn和Zn 饥饿。该提案的目的将评估这一假设并阐明金黄色葡萄球菌如何适应Mn 和Zn饥饿。 AIM I.阐明ARLRS监管网络的直接与间接目标 调节系统活动的环境信号。目标II。确定MN和Zn的影响 葡萄球菌中央代谢和碳源偏好的饥饿。目标三。阐明金属的方式 可用性会影响苏打和SODM对葡萄球菌疾病的贡献。实现这些目标 利用从微生物学和生物化学采取的技术以及一种跨学科的方法以及 将利用晚期元素定量和全细胞顺磁性光谱。