Coordination of metabolism and virulence during infection

感染过程中代谢和毒力的协调

• 批准号: 8214355
• 负责人: Brian M Ahmer
• 金额: $ 38.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214355
• 关键词: Acetates; Affect; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Behavior; Biochemical; Bioinformatics; Carbon; Cells; Complementary DNA; DNA; DNA Binding; Data; Developed Countries; Developing Countries; Disease; Environment; Escherichia; Exhibits; Formates; Future; Gammaproteobacteria; Gastroenteritis; Gel; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetic Translation; Genomics; Glucose; Glycogen; Immunocompromised Host; In Vitro; Infant; Infection; Intestines; Invaded; Klebsiella; Knowledge; Legionella; Life; Link; Location; Mediating; Metabolic; Metabolism; Methods; Microbial Biofilms; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Names; Nutrient; Organism; Orthologous Gene; Outcome; Paratyphoid Fever; Pathogenesis; Pathway interactions; Physiological; Play; Probiotics; Process; Processed Genes; Protein Biosynthesis; Proteins; Proteobacteria; Pseudomonas; RNA; RNA Sequences; RNA-Binding Proteins; Regulation; Regulator Genes; Regulon; Relative (related person); Reporter; Resistance; Role; SPI1 gene; Salmonella; Salmonella enterica; Salmonella infections; Seminal; Signal Transduction; Site; Staging; Stimulus; Stress; System; Systemic infection; Systems Biology; Testing; Type III Secretion System Pathway; Typhoid Fever; Untranslated RNA; Vaccine Design; Vibrio; Virulence; Volatile Fatty Acids; Work; Yersinia; base; cell motility; disease transmission; gastrointestinal infection; in vivo; mRNA Stability; mathematical model; member; mortality; novel; pathogen; prevent; promoter; quorum sensing; response; transcription factor

DESCRIPTION (provided by applicant): Salmonella infections are a significant cause of morbidity and mortality in both developed and developing nations. There are over 2600 serovars of Salmonella that exhibit a variety of host ranges and disease manifestations, which include gastroenteritis, bacteremia, metastatic infections and paratyphoid and typhoid fevers. In all cases, infection requires adaptation of the bacterium to distinct conditions of a number of host compartments, mediated in large part by changes in the expression of virulence and metabolism genes. Understanding these adaptations during the infection cycle is important for developing new strategies for preventing and treating infection. Although knowledge is limited, regulation of the virulence and metabolism genes of this organism are intricately linked through genetic circuitry involving SirA (Salmonella invasion regulator) and CsrA (carbon storage regulator). SirA is a DNA binding transcription factor that is the response regulator of the BarA-SirA two component signal transduction system. CsrA is an RNA binding protein that regulates mRNA translation and stability. CsrA activity is regulated by small noncoding RNAs (CsrB, CsrC), which sequester the CsrA protein. In turn, the transcription of csrB and csrC is activated by SirA. Regulation by this system responds to substrates and end products of carbon metabolism, which vary within host compartments, leading to the hypothesis that the status of carbon availability in large part governs adaptive transitions during the infection cycle. In Aim 1, a combination of genomic, bioinformatic, molecular genetic and biochemical approaches will be used to define the SirA and CsrA regulons, and thereby greatly increase our understanding of the regulatory links between metabolism and virulence. In Aim 2, several complementary approaches will be used to determine precisely when and where genes of this system are expressed and active during Salmonella infection of mice. This information will be evaluated in context with the regulons (defined in Aim 1) as well as the environmental and metabolic conditions that are known to influence these regulators in vitro. SirA and CsrA orthologs are highly conserved throughout the gamma-proteobacteria and are important for disease transmission and/or virulence in every species in which they have been examined. Thus, an understanding of the conditions and stimuli affecting SirA and CsrA activities and the mechanisms by which these proteins coordinate virulence and metabolic gene expression may be applicable to a broad range of pathogens. PUBLIC HEALTH RELEVANCE: Antibiotic therapies are relatively ineffective and are contraindicated for Salmonella gastrointestinal infections, which nevertheless have the potential to progress to life-threatening infections in infants and immunocompromised patients. Salmonella and many other species of bacteria utilize an ancient regulatory system to control metabolism and virulence. Determining the conditions that govern this regulatory system within the mammalian host, and determining the mechanisms and genetic circuitry by which this system functions may facilitate vaccine design and suggest novel targets and strategies for antibiotic and probiotic therapies.

描述（由申请人提供）：沙门氏菌感染是发达国家和发展中国家发病率和死亡率的重要原因。有超过2600多种血清沙门氏菌表现出各种宿主范围和疾病表现，其中包括胃肠炎，菌血症，转移性感染以及副肌肌动型和伤寒发烧。在所有情况下，感染都需要将细菌适应许多宿主室的不同条件，在很大程度上是通过毒力和代谢基因表达的变化来介导的。在感染周期中了解这些适应性对于制定预防和治疗感染的新策略很重要。尽管知识是有限的，但该生物体的毒力和代谢基因的调节通过涉及SIRA（沙门氏菌入侵调节剂）和CSRA（碳存储调节剂）的遗传回路神秘地联系在一起。 SIRA是DNA结合转录因子，它是Bara-Sira两个组件信号转导系统的响应调节剂。 CSRA是一种调节mRNA翻译和稳定性的RNA结合蛋白。 CSRA活性由小型非编码RNA（CSRB，CSRC）调节，该RNA隔离CSRA蛋白。反过来，CSRB和CSRC的转录被Sira激活。该系统的调节对碳代谢的底物和最终产物做出了反应，碳代谢在宿主室内各不相同，从而导致假设，即在很大程度上，碳供应状态在很大程度上控制着感染周期中的适应性过渡。在AIM 1中，将使用基因组，生物信息学，分子遗传和生化方法的结合来定义SIRA和CSRA调节，从而大大提高了我们对代谢和病情之间的调节联系的理解。在AIM 2中，将使用几种补充方法来确定在小鼠沙门氏菌感染期间表达该系统基因的何时何地。该信息将与规范（在目标1中定义）以及已知会影响这些调节剂体外影响这些调节剂的环境和代谢条件进行评估。 Sira和CSRA直系同源物在整个伽马细菌中高度保守，对于已检查的每种物种中的疾病传播和/或毒力都很重要。因此，对影响SiRA和CSRA活性的条件和刺激的理解以及这些蛋白质协调毒力和代谢基因表达的机制可能适用于广泛的病原体。 公共卫生相关性：抗生素疗法相对无效，并且是针对沙门氏菌胃肠道感染的禁忌，尽管如此，这些疗法仍然有可能发展为危及生命的婴儿和免疫功能低下的患者的感染。沙门氏菌和许多其他种类的细菌利用古老的调节系统来控制代谢和毒力。确定哺乳动物宿主中这种调节系统的条件，并确定该系统功能可以促进疫苗设计的机制和遗传回路，并提出了抗生素和益生菌治疗的新目标和策略。