Experimental assessment of wildlife viruses emergence potential through systematic characterization of human cell tropism

Emerging viruses pose a tremendous threat to human health and economy, as dramatically shown by the ongoing COVID-19 pandemic. Most emerging viruses are zoonotic, meaning that they can be transmitted between animal species and humans. Although it was estimated that more than one million viral species exist in the two main reservoirs of zoonotic viruses (mammals and birds), only a few hundred are known to infect humans. This means that the majority of wildlife viral species will likely not cause major outbreaks in the human population, but that many potentially human-infective viruses are lurking in nature. Although large-scale metagenomic studies allowed the identification of thousands of new viral species, functional data, including their ability to infect human cells, are often missing. Previous work has examined the human cell tropism of a fraction of wildlife viruses, but no systematic analysis of the factors involved in viral entry has been undertaken. In this proposal, we will use synthetic biology, experimental virology and viral evolution using a large number of human cell lines to implement a high throughput characterization of wildlife viruses' tropism. We will first test whether wildlife viruses'Äô envelopes from diverse viral families can mediate infection of a large panel of human cell lines. Comparing available transcriptomic data of susceptible and non-susceptible cell lines, we will identify novel wildlife viruses'Äô host entry factors. Finally, using experimental evolution, we will investigate how viral envelope natural selection and diversification impact the use of these newly identified entry determinants. Overall, this project should improve epidemic preparedness by identifying viral species or variants at higher risk to infect humans, as well as host factors participating to viral entry, which are potential targets for the development of antivirals.