Molecular Mechanisms of Macrophage Translational Regulation by Escherichia coli Lipopolysaccharide

大肠杆菌脂多糖调节巨噬细胞翻译的分子机制

• 批准号: 419469-2012
• 负责人: JaramilloPatino, Maritza
• 金额: $ 2.19万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630107
• 关键词: Molecular; Mechanisms; Macrophage; Translational; Regulation

Pathogenic bacteria, including Escherichia coli, express in their surface several toxins. One of them is called lipopolysaccharide (LPS). LPS is one of the most potent activators of a variety of immune cells, including macrophages. During bacterial infections, LPS interacts with proteins expressed in the macrophage surface named receptors. This event triggers a cascade of intracellular signals that lead to the induction of pro-inflammatory and anti-microbial molecules. Their production helps to protect the host against pathogen invasion. However, hyperactivation of the immune system can be detrimental and lead to death by endotoxin shock. Numerous studies have focused on how LPS stimulates transcription (RNA expression) of inflammatory and immune-responsive genes. In addition to transcriptional regulation, activation of RNA translation (protein synthesis) allows the cell to rapidly respond to infectious agents. Even though LPS triggers a robust and quick macrophage response, the contribution of translational control to such activation remains largely unexplored. Therefore, the current research program designed to identify the RNAs associated to inflammation and immunity, which are controlled by LPS at the translational level. We also aim to dissect the intracellular signals involved. To this end we will deploy a combination of biochemical, molecular biology and genetic experimental approaches. The stimulation of macrophage activation by LPS constitutes an excellent model of inflammation and has greatly contributed to understand how the host cell, and ultimately the immune system of patients, responds to infectious agents. Our data will shed light on the importance of translational control in response to bacterial toxins, which will aid the advance of knowledge on the molecular mechanisms that govern host -pathogen interactions. Importantly, our work will contribute to establish whether regulators of translation could become new therapeutic targets for treatments against bacterial infections and thereby improve the life quality of Canadians.

致病细菌，包括大肠杆菌，在其表面表达几种毒素。其中一种称为脂多糖（LPS）。LPS是多种免疫细胞（包括巨噬细胞）的最有效的激活剂之一。在细菌感染期间，LPS与巨噬细胞表面表达的称为受体的蛋白质相互作用。这一事件触发了一系列细胞内信号，导致促炎和抗微生物分子的诱导。它们的产生有助于保护宿主免受病原体入侵。然而，免疫系统的过度激活可能是有害的，并导致内毒素休克死亡。许多研究都集中在LPS如何刺激炎症和免疫应答基因的转录（RNA表达）。除了转录调控，RNA翻译（蛋白质合成）的激活使细胞能够快速响应感染因子。尽管LPS触发了一个强大的和快速的巨噬细胞反应，翻译控制这种激活的贡献仍然在很大程度上未被探索。因此，目前的研究计划旨在鉴定与炎症和免疫相关的RNA，这些RNA在翻译水平上由LPS控制。我们还旨在剖析所涉及的细胞内信号。为此，我们将部署生物化学，分子生物学和遗传实验方法的组合。LPS对巨噬细胞活化的刺激构成了极好的炎症模型，并且极大地有助于理解宿主细胞以及最终患者的免疫系统如何对感染因子做出反应。我们的数据将阐明翻译控制在细菌毒素反应中的重要性，这将有助于提高对宿主-病原体相互作用的分子机制的认识。重要的是，我们的工作将有助于确定翻译调节因子是否可以成为治疗细菌感染的新靶点，从而改善加拿大人的生活质量。