The interface between metabolism and virulence in environmental pathogens

环境病原体代谢与毒力之间的界面

基本信息

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：
2019
资助国家：
加拿大
起止时间：
2019-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684104
关键词：
interface between metabolism virulence environmental

项目摘要

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。一个显着的例子是洋葱伯克霍尔德氏菌复合体（Bcc），这是一组革兰氏阴性细菌，其特征是多功能分解代谢，能够在不同的环境中定殖并与多个宿主相关，包括患有遗传性疾病囊性纤维化（CF）的人类。在我之前的 NSERC 发现计划中，我在氨基酸消耗和细菌毒力之间建立了一种新的关联。我发现苯丙氨酸分解代谢的中间体苯乙酸 (PAA) 可以调节 Bcc 群体感应 (QS) 反应，从而调节毒力。该 NSERC 研究计划将扩展感染条件下的氨基酸分解代谢，重点关注 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与群体感应调节剂结合，以及确定的相互作用是否改变它们对毒力基因的调节作用。 Cenocepacia 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 相关毒力下调的生物学意义，我们将研究低氧条件下苯丙氨酸降解对 QS 介导的致病性的贡献，其中 Bcc 中的 PAA 降解可能被消除。 B. cenocepacia 能够在植物模型拟南芥中引起感染，从而可以在植物与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，作为其防御机制的一部分，可能在植物中下调。为了探索 B. cenocepacia 是否可以产生 PAA 样分子来增强植物对感染的敏感性，我们将使用拟南芥宿主模型并监测感染了新洋葱 B. cenocepacia 突变体的植物的疾病进展，该突变体在 PAA 分解代谢的各个阶段被阻断。* *****这项研究将建立 PAA 分解代谢调节 QS 的分子基础，阐明两种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、人类和植物相关的微生物相互作用过程中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将为跨学科研究提供一些培训机会，这在工业界和学术界都有很高的需求。识别营养物质的使用与 QS 之间的分子机制将揭示干预成分作为治疗或生物技术干预的可能目标。 **********