Understanding the reprogramming of host mRNA translation during calicivirus infection

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Our overarching aim is to understand the mechanism by which a group of poorly characterised, yet important viruses, regulate host gene expression to modulate how cells respond to viral infection Cells within the body respond to environmental stimuli and pathogen infection in many ways, the most common of which is via the regulation of cellular gene expression. The expression of the information stored in our genes is tightly controlled at numerous levels, to ensure that the correct protein is produced at the right time and quantity. First, the genetic information encoded in our DNA is converted into messenger RNA (mRNA), via a process called transcription. The mRNA is then "translated" into proteins by structures referred to as ribosomes, assisted by proteins called initiation factors. eIF4E is one of these proteins and its key role is to direct the ribosomes and other proteins to the mRNA. This process is called translation and the synthesised proteins make our cells what they are, defining their properties and functions. Importantly, changes to the proteins in our cells also help to fight against invading pathogens such as viruses. While viruses can infect most organisms and cause severe damage, they consist primarily of RNA or DNA enclosed in a protein coat and lack the factors required for replication and dissemination. They are therefore dependent on the host cell resources to produce viral proteins. Thus, many viruses have developed strategies that regulate the function of the host protein synthesis machinery, often leading to preferentially translation of viral mRNAs. Caliciviruses are a family of small viruses that can cause diseases both in humans and animals. In humans they primarily cause gastroenteritis. While the human norovirus, a calicivirus, does not grow well in cell culture, murine norovirus, a mouse homologue, acts as model with which to study many aspects of calicivirus biology in the laboratory. It represents an excellent model to dissect how viruses affect the translation of host cell proteins. Using this model we have previously made a number of significant advances in the understanding of how the caliciviruses produce viral proteins. We found that a virus-encoded protein, called VPg, is essential for the translation of viral mRNA as it coordinates the recruitment of host proteins to the viral RNA. We also showed that calicivirus infection modulates the composition and activity of the host translation machinery. However, we still know very little about how pathogens in general, and caliciviruses in particular, modulate the translation of host mRNAs during infection. This is important because understanding the modulation of specific host mRNA translation by viruses can reveal how viruses manipulate the organism's response to infection. Our hypothesis is that caliciviruses alter the translation of specific mRNAs in the infected host to regulate antiviral gene expression, and that they do so by modulating the translation factor eIF4E. Therefore, our objectives are to use high-throughput sequencing and biochemical methods to 1- characterize how the viral infection alters the profile of mRNAs that are translated by the infected host and 2- to understand how the activity of eIF4E is regulated by caliciviruses during this process. If we can fully understand how caliciviruses control the activity of translation factors and reprogramme the host protein synthesis, we can identify ways to inhibit virus replication. Therefore, our work will aid in the development of novel antiviral therapies for this important group of viruses, and perhaps other viruses that regulate translation. Understanding the fundamental mechanisms of gene regulation is important not only for virologists but also for broader academic communities. By advancing our basic knowledge of translational control we may understand better several pathologies that are linked to modulation of eIF4E activity, such as cancer and diabetes.