Harnessing the host innate immune response against single stranded RNA-positive emerging viruses.

Emerging viral diseases pose a major threat to public health worldwide. This continuous emergence of new viruses with zoonotic circulation, their high transmissibility, the severity of related pathologies in humans, and the lack of available drugs is a tremendous challenge for public health systems. For these reasons, there is a critical need of research networks aimed at understanding the virological and cellular mechanisms that drive viral replication and contribute to the activation of an excessive inflammatory response underlying the severe symptoms. This proposal aims at increasing our understanding of the complex interplay between ssRNA+ viruses and host target cells and how it affects viral replication and the inflammatory cascade that is triggered upon infection. It will focus on multiple host factors, including molecules involved in lipid metabolism, extracellular vesicle composition, viral sensing, and restriction factors, to unveil their role in controlling the virus life cycle or in tuning the cellular response to infection. The project goals will be achieved through the integrated cooperation of three Research Units (RUs) with different and complementary skills in virus-host interactions, molecular virology, immunology, and molecular and cell biology. Each RU will contribute to the project success by sharing in vitro cellular models e.g. IFI16 knockout cells, NAAA knockout cells, and innovative technologies e.g. high-content confocal screenings or trascriptome profiling. The experimental activities will be primarily focused on human Coronavirus infection, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and NL-63, and Flavivirus, specifically Zika virus (ZIKV) and West Nile virus (WNV). The results obtained will contribute to the discovery of new druggable targets or drugs that are able to block specific host cell pathways that are essential for viral infection, without affecting cell functions. This host-targeted approach may represent an excellent tool to obtain safe and broad-spectrum antivirals and to overcome virus-induced drug resistance that is one of the main limitations of the available antiviral therapy. As an additional benefit, the team is composed of young scientists committed to carry on and expand the project and build a highly stimulating scientific environment. Moreover, considering the large proportion of female scientists involved in this project, this can also be considered as a model of their retention in leadership positions.