Dissecting the host cellular response to develop novel host-targeted approaches against RNA viruses

Over the last one hundred years, the world has faced ten pandemics. The viral families Orthomyxoviridae and Coronaviridae were responsible for eight of them. The influenza virus sustains itself in the population through antigenic drift mechanisms escaping immune response and it is a permanent threat for its ability to generate new pandemic viruses. SARS-CoV, MERS-CoV, and SARS-CoV-2 are pandemic coronaviruses that have caused millions of deaths in recent years. Other factors, such as climate change, globalization, and high population density expand the list of viruses with the pandemic potential to arboviruses, rodent-borne viruses, and other RNA viruses. SARS-CoV-2 pandemic has also clearly demonstrated that we need better preparedness to face future unavoidable pandemics. This is achieved through the understanding of viral and host responses, production of efficient vaccines, and development of broad-spectrum antivirals. The definition of viral and host responses and broad-spectrum antivirals are crucial to containing disease burden while vaccines are being developed. Hearthen, from Host cEllulAr Response hosT-targEted rNa, aims to gain insights into host cell responses and pathways controlling replication of RNA viruses with a high pandemic or pathogenic potential. The overarching goal is to dissect the role of redox-regulated pathways, components of sugar and lipid metabolisms, viral sensors, and restriction factors in the modulation of both viral replication and cellular response. Ultimately, these studies will allow the unveiling of new therapeutic cellular targets for the development of antiviral/anti-inflammatory approaches. The mission will be accomplished by a team of three Research Units (RUs), which already work together and have complementary and integrated expertise on virus-host interactions, molecular virology, immunology, molecular and cellular biology, and bioinformatics. Each RU will contribute to Hearthen by sharing ideas, results, viruses, cellular models, technologies, and instruments. The experimental activities are organized in three workpackages (WPs). In WP1, the aforementioned cellular factors/pathways will be analysed for their impact on the replication of selected RNA viruses with pandemic potential in cellular models developed ad hoc. In WP2, the same setting is used to gain more insight into the molecular mechanisms underlying host cell responses. These WPs will enhance our understanding of the cellular pathways triggered in response to RNA virus infections, their crosstalk, and the impact on viral replication. The deliverables will be exploited in WP3 to develop novel host-targeted approaches as a tool to generate safe and broad-spectrum antivirals. Lastly, Hearthen will also contribute to the career development of talented young scientists in leadership positions.