Experimental Virology Assessing Tender

Grant agreement ID 101019724Start date 1 May 2022End date 30 April 2027Overall budget 2 436 500 ObjectiveThe 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.