Project Summary/Abstract Animal viruses share two important features; a) an efficient system for delivering their genome to the targetcell usually involving an activation process in the virion and b) a means of interacting with the adaptive immunesystem of the host. The structural and biophysical studies detailed here will show how the noroviruses haveevolved capsids that perform both functions. Human noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. Norovirusesgenerate new strains every 2-4 years that cause worldwide epidemics. In the US alone, annually there are ~20million cases and more than 70,000 hospitalizations of children. Efforts for a vaccine have been hindered by alack of detailed structural information about antibody binding and the mechanisms of antibody escape. Inaddition, containment of the disease is also problematic since as few as ten virions are sufficient to infect anormal adult. Understanding all of these processes has been difficult with human noroviruses because of thelack of a tissue culture system and small animal model. To this end, we will be using the highly tractablemouse norovirus system where we have a cell culture system and an infectious clone. With regard to the first function of a viral capsid, we present evidence that noroviruses appear to undergoan apparent activation process where the addition of bile salts causes the protruding domain (P domain) torotated and move ~16Ã… onto the surface of the shell. This movement is correlated with greatly enhancedbinding of the virus to the cell. In terms of the second function of a viral capsid, we also present evidence thatthe P domain itself is highly plastic and that this motility plays an integral role in receptor binding and antibodyescape. Therefore, the studies presented here will not only elucidate a very unique norovirus activationprocess, but also how the virus evades the immune system. Together, this information could be leveraged inthe future to develop vaccines and therapeutics for this serious disease.