Molecular Mechanisms of Macrophage Translational Regulation by Escherichia coli Lipopolysaccharide

病原体，包括大肠杆菌，在它们的表面表达几种毒素。其中一种被称为脂多糖(LPS)。脂多糖是包括巨噬细胞在内的多种免疫细胞最有效的激活剂之一。在细菌感染期间，内毒素与巨噬细胞表面表达的蛋白质相互作用，称为受体。这一事件触发了一系列细胞内信号，导致了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，并通过内毒素休克导致死亡。许多研究都集中在内毒素如何刺激炎症和免疫反应基因的转录(RNA表达)。除了转录调控外，RNA翻译(蛋白质合成)的激活使细胞能够对感染性病原体迅速做出反应。尽管脂多糖触发了强大而快速的巨噬细胞反应，但翻译调控对这种激活的贡献在很大程度上仍未被探索。因此，目前的研究计划旨在识别与炎症和免疫相关的RNA，这些RNA在翻译水平上受内毒素控制。我们还打算剖析所涉及的细胞内信号。为此，我们将采用生物化学、分子生物学和遗传学实验相结合的方法。内毒素刺激巨噬细胞激活构成了一个很好的炎症模型，并极大地有助于了解宿主细胞，最终患者的免疫系统，如何对感染性病原体做出反应。我们的数据将有助于阐明翻译控制对细菌毒素反应的重要性，这将有助于进一步了解控制宿主-病原体相互作用的分子机制。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治疗靶点，从而提高加拿大人的生活质量。

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.