Molecular Mechanisms of Macrophage Translational Regulation by Escherichia coli Lipopolysaccharide

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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.