Descrizione del progetto
Studiare le minacce virali zoonotiche
I virus degli animali selvatici sono una minaccia reale per la salute pubblica, come dimostrato dalle epidemie di Ebola e dalla pandemia di COVID-19. Tuttavia, si sa poco su come funzionano tali virus. Il progetto EVADER, finanziato dall’UE, studierà l’insorgenza virale da un punto di vista evolutivo. Studiando come i mutanti dello spettro d’ospite appaiono e si adattano alle cellule umane, fornirà il panorama più completo dell’infettività virale delle cellule umane fino ad oggi. Il progetto studierà anche il tropismo cellulare dipendente dai recettori dei virus RNA avvolti, un processo sperimentalmente trattabile coinvolto nell’insorgenza virale. Infine, fornirà importanti indizi sul ruolo della mutazione spontanea nell’insorgenza virale ed esplorerà la fattibilità di terapie antivirali a livello di clade.
Obiettivo
The emergence of new human pathogenic viruses from animal reservoirs is an increasing concern, but also a poorly understood process. Massive sequencing programs have been recently launched to characterize wildlife viruses, but empirical information on how these viruses function and whether they can potentially infect humans is needed. However, the isolation and culturing of wildlife viruses is too often unfeasible due to technical issues, biosafety concerns, or lack of full-length sequence information. Furthermore, we need to investigate viral emergence from an evolutionary standpoint to better understand how host-range mutants appear and adapt to human cells. To achieve these goals, we will focus on the receptor-dependent cell tropism of enveloped RNA viruses, a central and experimentally tractable process involved in viral emergence. First, we will use high-throughput gene synthesis to create hundreds of pseudoviruses coated with the envelopes of previously uncharacterized wildlife viruses belonging to different families, and we will examine their ability to infect a panel of humans cells from various tissues. This will deliver the most comprehensive landscape of viral human cell infectivity to date. Second, we will use experimental evolution, massive parallel sequencing, and site-directed mutagenesis to explore how viral envelopes diversify, undergo cell tropism shifts, and adapt to human cells. This will provide important clues about the role of spontaneous mutation in viral emergence, and may reveal repeatable evolutionary pathways that could help us improve outbreak predictability. Finally, we will use our experimental results to infer candidate cell receptors for wildlife viruses using machine learning, and to explore the feasibility of broad-range, clade-level antiviral therapies that could be used for combating emerging viruses in the future.
Campo scientifico
- medical and health scienceshealth sciencesinfectious diseasesRNA viruses
- natural sciencesbiological sciencesmicrobiologyvirology
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- natural sciencescomputer and information sciencesartificial intelligencemachine learning
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
46010 Valencia
Spagna