When a virus infects a human cell, the cell slams the brakes on nearly all protein production to starve the invader—yet somehow still churns out its own antiviral defence proteins. This study aims to explain how cells pull off that contradictory feat. The problem is a fundamental gap in knowledge. Scientists understand how cells shut down general protein synthesis during an antiviral response, but they do not know how the cell’s protein-making machinery—ribosomes and tRNA molecules—selectively keeps producing defensive proteins while everything else stops. Without that understanding, efforts to boost natural antiviral defences or block viral hijacking of protein production remain incomplete. This is fundamental science with no immediate practical application. The researcher will use tRNA sequencing, ribosome profiling, and mass spectrometry to map changes in the cell’s translation machinery over the course of an antiviral response in human cells, then test which of those changes are functionally important for selective defence-protein production. If successful, the work could reveal new molecular targets for broad-acting antiviral therapies that strengthen the cell’s intrinsic defences rather than attacking specific viruses.
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Viruses are a major threat to human health and wellbeing. The cellular antiviral response represents the first line of defence against viruses. Characterising intrinsic cellular defences is necessary for the development of new broad-acting antiviral treatments. Central to the cellular antiviral response is the generalised shutdown of protein production, or translation, within the cell. Viruses are entirely reliant on cellular protein production machinery. Generalised translational shutdown in an infected cell helps limit viral replication and spread. However, at the same time, cells must produce a host of antiviral defence proteins that inhibit viral activity directly. Balancing these two contradictory processes, while also limiting viral manipulation of protein production, can determine the outcome of viral infection. While the regulatory mechanisms that drive translational shutdown are well understood, far less is known about those allowing concurrent selective translation of antiviral proteins. In this research study, I will examine how changes in the cellular translational machinery itself could drive the selective production of defensive antiviral proteins during host translational shutdown. I will focus on the core components of the translational machinery: ribosomes, the large macromolecular machines that carry out protein synthesis, and tRNAs, the adaptor molecules that decode genetic instructions into protein. Changes in the cellular tRNA pool and ribosomal populations can drive the expression of specific proteins in various contexts, including cancer metastasis and embryogenesis. Moreover, viruses and infected host cells have been shown to manipulate tRNAs and ribosomes to affect the outcome of infection. However, we do not have a comprehensive characterisation of the extent and impact of changes to the tRNA pool and ribosomal population during the antiviral response. I hypothesise that cells specialize their tRNA pool and ribosomal population to enable selective translation of defensive proteins during the antiviral response. To test this hypothesis, I will use tRNA sequencing, ribosome profiling, and mass spectrometry-based protein identification to generate a high-resolution picture of the tRNA pool and ribosomal population over the course of the antiviral response in human cells. I will identify significant features of this antiviral translational machinery and characterise their functional relevance in the selective translation of host defence proteins. This project will provide insight into a key component of the antiviral response and will elucidate mechanisms by which regulation of the translational machinery can affect cell fate and function. Understanding what drives selective translation during the antiviral response will improve our ability to therapeutically bolster cellular antiviral defences and impede viral manipulation of cellular protein production.
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