The interface between metabolism and virulence in environmental pathogens

环境病原体代谢与毒力之间的界面

• 批准号: RGPIN-2016-05924
• 负责人: Cardona, Silvia
• 金额: $ 2.26万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615992
• 关键词: interface; between; metabolism; virulence; environmental

Environmental pathogens are microorganisms that live outside the human host but can gain access to the human body and cause disease. A remarkable example is the Burkholderia cepacia complex (Bcc), a group of Gram negative bacteria characterized by versatile catabolism, the ability to colonize diverse environments and associate with several hosts, including humans with the genetic disease cystic fibrosis (CF). In my previous NSERC Discovery program, I established a novel association between amino acid consumption and bacterial virulence. I discovered that an intermediate of phenylalanine catabolism, phenylacetic acid (PAA), modulates the Bcc quorum sensing (QS) response, which in turn regulates virulence. This NSERC research program will expand on amino acid catabolism during infection conditions with a focus on the biological significance of PAA-mediated regulation of QS. My laboratory will use molecular biology tools and structural analysis to investigate whether PAA and other phenylalanine catabolism intermediates bind to quorum sensing regulators, and whether the identified interactions change their regulatory effect on virulence genes. B. cenocepacia, one of the species of the Bcc, can grow in the microoxic, amino acid-rich mucus of the CF lung and establish a chronic infection. To address the biological significance of PAA-related downregulation of virulence, we will investigate the contribution of phenylalanine degradation to QS-mediated pathogenicity in low oxygen conditions, where PAA degradation in Bcc may be abolished. B. cenocepacia is able to cause infection in the plant model Arabidopsis thaliana, allowing exploration of phenylalanine and PAA metabolism during a plant-bacteria interaction. PAA is a phytohormone and may be downregulated in plants as part of their defense mechanisms. To explore if B. cenocepacia can produce PAA-like molecules that enhance plant susceptibility to infection, we will use the A. thaliana host model and monitor disease progression in plants infected with B. cenocepacia mutants blocked at various stages of the PAA catabolism. This research will establish the molecular basis of QS regulation by PAA catabolism, elucidating a novel link between two conserved bacterial features. The diverse pathogenic interactions of Bcc allow the use of plant and animal models. Thus, our findings will have broad implications for microbial metabolism during animal, human and plant-related microbial interactions. The cross-feeding between functional genomics, chemistry, and molecular biology will provide several training opportunities for interdisciplinary research, which is in high demand in the industry and academic sectors. Identification of the molecular mechanisms that connect the use of nutrients with QS will expose the intervening components as possible targets for therapeutic or biotechnological interventions.

环境病原体是生活在人类宿主之外但可以进入人体并引起疾病的微生物。一个了不起的例子是Burkholderia cepacia复合物（BCC），这是一组具有多功能分解代谢的革兰氏阴性细菌，具有殖民环境并与多个宿主相关的能力，包括具有遗传疾病囊肿纤维化（CF）的人类。在我以前的NSERC发现计划中，我建立了氨基酸消耗和细菌毒力之间的新型关联。我发现苯丙氨酸分解代谢，苯乙酸（PAA）的中间体调节了BCC法定感应（QS）反应，进而调节毒力。该NSERC研究计划将在感染条件下扩展氨基酸分解代谢，重点是PAA介导的QS调节的生物学意义。 我的实验室将使用分子生物学工具和结构分析来研究PAA和其他苯丙氨酸分解代谢中间体是否与法规传感调节剂结合，以及确定的相互作用是否改变了其调节性对毒力基因的影响。 B. cenocepacia是BCC的物种之一，可以在CF肺的微氧，富含氨基酸的粘液中生长，并建立慢性感染。为了解决与PAA相关的毒力下调的生物学意义，我们将研究苯丙氨酸降解对QS介导的低氧条件下的QS介导的致病性的贡献，其中可能会废除BCC中的PAA降解。 Cenocepacia能够在植物模型拟南芥中引起感染，从而允许在植物 - 细菌相互作用期间探索苯丙氨酸和PAA代谢。 PAA是一种植物激素，可以作为其防御机制的一部分在植物中下调。为了探索Cenocepacia是否可以产生类似PAA的分子，从而增强植物对感染的敏感性，我们将使用A. thaliana宿主模型并监测被PAA分解代谢的各个阶段被阻塞的Cenocepacia突变体感染的植物中的疾病进展。 这项研究将通过PAA分解代谢来建立QS调节的分子基础，从而阐明了两个保守细菌特征之间的新联系。 BCC的多种致病相互作用允许使用动植物模型。因此，我们的发现将对动物，人类和植物相关的微生物相互作用期间的微生物代谢具有广泛的影响。功能基因组学，化学和分子生物学之间的交叉进食将为跨学科研究提供一些培训机会，跨学科研究在行业和学术领域的需求很高。鉴定将营养物质与QS的使用相关的分子机制将使中间成分作为治疗或生物技术干预措施的可能目标。