The evolutionary genetic basis for changes in viral receptor-binding specificities

Project Summary/Abstract In this proposal, I discuss my plans to use a high-throughput yeast display platform to dissect the essential changes that occur in viral protein binding specificities. I am using the coronavirus family for my investigations because there are instances of species specificity changes of interest in the SARS-related coronaviruses that are of interest, as well as instances of wholesale receptor changes in the MERS-related coronaviruses. Thus far, this work has begun to find the substitutions of interest along the gains of human ACE2 binding in the SARS-related coronaviruses. From preliminary results, we can see one substitution that is highly associated with mutations that can bind human ACE2. In addition, I have started to parse out the important branch where the wholesale receptor change occurred along the MERS-related coronavirus family phylogenetic tree. These changes are particularly interesting because the evolutionary genetic basis for these receptor-binding specificity changes has not been characterized. Through this research, I will inform the field of the necessary changes that need to occur for viruses to switch receptors as well as what effects species specificity has on these receptor binding dynamics. Overall, this work will be important for the field, too, because it will lay a foundation of how these viruses are gaining the ability to spillover from their animal reservoirs and into humans. Zoonotic transmission, or viruses gaining the ability to bind human receptors, is a major threat to human health, as we know from the SARS-CoV-2 pandemic and the MERS epidemic, for instance.