RNAdeg-Virus · Elucidating how XRN1-mediated RNA degradation controls virus infection

Elucidating how XRN1-mediated RNA degradation controls virus infection

Every living organism is in a constant and fierce battle with viruses, which are obligate intracellular pathogens that require the cellular resources of the host to replicate and generate new viral progeny. These sub-living entities constitute a major threat for health and a burden for countries’ economies. Arboviruses are transmitted to human by arthropods and represent one of the most prominent biomedically relevant group of viruses. Due to global warming and increased urbanization, arthropods habitats are expanding and arboviruses are reaching non-endemic areas causing new epidemies. Viruses have been intensively studied since many years to understand the origin of their existence, their biological cycles, and the consequences of their infection. Due to the potential threat caused by these entities it is critical to understand the replication steps of these viruses in order to develop more effective therapies, since relatively few therapeutic options are available and only for a limited scope of viruses. Since viruses only possess very limited genetic instructions on their own, they strongly rely on cellular resources and tools, thus it bears extreme importance to study the virus-host interaction. RNA binding proteins (RBPs) mediate numerous critical steps for the codification of the genetic information. In the past few years RBPs emerged as central regulators of infection, controlling virtually every step of the viral cycle, and it is essential to deeply understand their interconnection with viruses. To investigate the virus-host interaction and gain a better understanding of the viral replication, I employed Sindbis virus (SINV), an arthropod-borne virus transmitted to human through the bite of mosquitoes, as a discovery model. In a recent scientific breakthrough, it has been highlighted that SINV requires the presence of a host RBP called 5’-3’ exoribonuclease 1 (XRN1), a master regulator of gene expression, in order to infect cells. Also, SINV infection causes a global downregulation of gene expression concomitant with a pervasive degradation of cellular RNA. With RNAdeg-Virus project, I aim to understand the molecular mechanism of SINV infection regulated by XRN1. (i) I set to understand if XRN1 is the driving force rewiring the transcriptome of a cell, (ii) what is the trigger for XRN1 activity, and (iii) the biological significance of its role during infection. By the use of a multidisciplinary approach I am clarifying the molecular mechanism of XRN1 regulation of SINV infection, and also generating numerous datasets that will spark the creativity of several future scientific projects. The knowledge generated by this work will be the stepping stone for future discoveries which will improve human health and have a strong impact on society. In addition, this project brought us a step closer to the development of specific antiviral drugs potentially acting on a broad range of viruses.

Data: CORDIS, © European Union