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的微生物，但可以进入人体并引起疾病。一个值得注意的例子是洋葱伯克霍尔德菌复合体（Bcc），一组革兰氏阴性细菌，其特征是多功能的catalysts，能够定殖不同的环境并与几种宿主，包括患有遗传疾病囊性纤维化（CF）的人类。在我之前的NSERC发现计划中，我建立了氨基酸消耗和细菌毒力之间的新联系。我发现苯丙氨酸催化剂的中间体苯乙酸（PAA）调节Bcc群体感应（QS）反应，进而调节毒力。这个NSERC的研究计划将扩大在感染条件下的氨基酸catalysts，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和其他苯丙氨酸催化剂中间体是否与群体感应调节剂结合，以及所确定的相互作用是否改变其对毒力基因的调节作用。B。新洋葱虫是Bcc的一种，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的贡献，在低氧条件下，在BCC中PAA降解可能被废除的QS介导的致病性。B。cenocepacia能够在植物模型拟南芥中引起感染，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，在植物中可能作为其防御机制的一部分被下调。去探索如果B。cenocepacia可以产生PAA样分子，增强植物对感染的易感性，我们将使用A。并监测感染B植物中的疾病进展。cenocepacia突变体在PAA催化剂的各个阶段被阻断。 这项研究将建立由PAA催化剂的QS调节的分子基础，阐明两个保守的细菌特征之间的新联系。Bcc的多种致病相互作用允许使用植物和动物模型。因此，我们的研究结果将对动物，人类和植物相关微生物相互作用期间的微生物代谢产生广泛的影响。功能基因组学，化学和分子生物学之间的交叉喂养将为跨学科研究提供几个培训机会，这在工业和学术部门都有很高的需求。鉴定将营养素的使用与QS联系起来的分子机制，将使干预成分成为治疗或生物技术干预的可能靶点。