Investigating the role of conserved signaling modules in medically important Acinetobacter species

研究保守信号模块在医学上重要的不动杆菌物种中的作用

• 批准号: 10461786
• 负责人: Ramiro Patino
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461786
• 关键词: Accounting; Acinetobacter; Acinetobacter Infections; Acute; Adenylate Cyclase; Afghanistan; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biochemical; Bioinformatics; Biological Assay; Cellular biology; Chemicals; Complex; Critical Illness; Cues; Cyclic AMP; Cyclic AMP Receptor Protein; Disease; Environment; Escherichia coli; Exhibits; Genes; Genetic Transcription; Genome; Grant; Growth; Homologous Gene; Homologous Protein; Human; Immunocompetent; Individual; Infection; Iraq; Knowledge; Life Style; Liquid substance; Locomotion; Mediating; Medical; Methods; Microscopy; Morbidity - disease rate; Multi-Drug Resistance; Nosocomial Infections; Output; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Physiology; Pilum; Pneumonia; Process; Production; Proteins; Pseudomonas aeruginosa; Public Health; Resistance; Role; Second Messenger Systems; Signal Transduction; Soft Tissue Infections; Solid; Surface; System; Technology; Testing; Type II Secretion System Pathway; Virulence; Virulence Factors; Work; bacterial genetics; base; cell motility; experimental study; healthcare-associated infections; human disease; innovation; insight; interest; mortality; mutant; novel; opportunistic pathogen; pathogen; pathogenic bacteria; prevent; programs; response; transcriptome; transcriptome sequencing; transcriptomics; wound; wounded soldier

Project summary Medically important Acinetobacter species are opportunistic bacterial pathogens that can cause devastating disease in hospitalized patients and are responsible for ~2% of nosocomial infections in the US. These species are emerging as a public health threat worldwide due to their tendency to exhibit multidrug-, or even, pandrug-resistance. Therefore, we urgently need to develop new methods to treat and prevent MDR Acinetobacter infections. Critical for this advance is a detailed understanding of how these species cause human disease; however, much remains to be learned about the pathogenesis of Acinetobacter infections. Importantly, The Engel lab and others have identified three systems in Pseudomonas aeruginosa, another important opportunistic pathogen, that coordinately activate a virulence program in response to surface contact. These systems include the type IV pilus (TFP), the Chp chemosensory system, and the cAMP/Vfr axis. Together, these modules regulate twitching motility and expression of >200 virulence genes, such as the type II secretion system. It is intriguing that P. aeruginosa repurposed and combined together three distinct modules to regulate an acute virulence program when in other bacteria the TFP and the cAMP/Vfr axis control other processes. To test whether other bacteria utilize similar components and similar circuitry, the Engel lab performed a bioinformatics analysis to determine whether these modules were conserved and present together in other bacteria. Of high interest was the finding that medically important Acinetobacter species encode homologs of all three of these modules. Given the remarkable similarity in the lifestyles of Acinetobacter species and P. aeruginosa, including their ability to survive in diverse environments as well as to cause similar diseases in humans, I hypothesize that these three systems function coordinately to regulate the ability of a pathogenic Acinetobacter species to survive in diverse environments and to cause human disease. In Aim 1, I will use a combination of bacterial genetics, biochemical, and innovative microscopy assays to establish the functional outputs of the Acinetobacter Chp system and to determine if it is interconnected to the TFP and cAMP/Vfr modules. In Aim 2, I will make use of transcriptomic technologies to identify the virulence genes regulated by the Acinetobacter Vfr transcriptional regulator and to elucidate if Vfr activation depends on the TFP and Chp system modules. Taken together, these aims will allow me to determine whether the TFP, the Chp chemosensory system, and the cAMP/Vfr modules work together to regulate virulence in Acinetobacter species. These studies may identify new targets to develop novel antibiotics, and they might also provide a better understanding of the physiology and cell biology of medically important Acinetobacter species.

项目概要 医学上重要的不动杆菌属是机会性细菌病原体，可导致 它是住院患者的毁灭性疾病，约占美国医院感染的 2%。 这些物种由于表现出多种药物或多种药物的倾向，正在成为全世界的公共卫生威胁。 甚至，泛耐药性。因此，我们迫切需要开发治疗和预防MDR的新方法 不动杆菌感染。这一进步的关键是详细了解这些物种如何导致人类 疾病;然而，关于不动杆菌感染的发病机制还有很多东西有待了解。重要的是， 恩格尔实验室和其他人已经在铜绿假单胞菌中发现了三个系统，这是另一个重要的系统。 机会性病原体，协调激活毒力程序以响应表面接触。这些 系统包括 IV 型菌毛 (TFP)、Chp 化学感应系统和 cAMP/Vfr 轴。在一起，这些 模块调节抽搐运动和超过 200 个毒力基因的表达，例如 II 型分泌系统。 有趣的是，铜绿假单胞菌重新利用并组合了三个不同的模块来调节急性 在其他细菌中，TFP 和 cAMP/Vfr 轴控制其他过程时的毒力程序。测试是否 其他细菌利用相似的组件和相似的电路，恩格尔实验室进行了生物信息学分析 以确定这些模块是否保守并一起存在于其他细菌中。兴趣浓厚 发现医学上重要的不动杆菌属编码所有这三个模块的同源物。 鉴于不动杆菌属和铜绿假单胞菌的生活方式非常相似，包括它们的能力 为了在不同的环境中生存并在人类中引起类似的疾病，我假设这三种 系统协调发挥作用，调节致病性不动杆菌在不同环境中的生存能力 环境并导致人类疾病。在目标 1 中，我将结合细菌遗传学、生化、 和创新的显微镜检测，以确定不动杆菌 Chp 系统的功能输出，并 确定它是否与 TFP 和 cAMP/Vfr 模块互连。在目标 2 中，我将利用转录组学 鉴定由不动杆菌 Vfr 转录调节因子调节的毒力基因的技术 阐明 Vfr 激活是否取决于 TFP 和 Chp 系统模块。总而言之，这些目标将使 我确定 TFP、Chp 化学感应系统和 cAMP/Vfr 模块是否协同工作 调节不动杆菌属的毒力。这些研究可能会确定开发新型抗生素的新目标， 它们还可能使人们更好地理解具有医学重要性的生理学和细胞生物学 不动杆菌属。