Structural basis for human astrovirus entry

PROJECT SUMMARY Human astroviruses (HAstV) are a leading cause of viral diarrhea in children. Currently, no vaccines or antiviral therapies exist for HAstV infections. Our goal is to identify essential functional sites on the HAstV surface that can be exploited for the development of preventative and therapeutic strategies against HAstV. The HAstV virion is a small, icosahedral virus composed of an RNA genome surrounded by capsid protein. HAstV enters cells through clathrin-mediated endocytosis. The human neonatal Fc receptor (FcRn) was recently identified as a functional receptor for HAstV entry into human cells, and dipeptidyl-peptidase IV (DPP4) was identified as a cofactor for HAstV entry. However, the molecular basis for HAstV interaction with these receptors is unknown, and the mechanism by which these receptors promote virus entry is unknown. Our central hypothesis is that the HAstV capsid spike domain engages FcRn in the endosome to promote virus genome release. Using innovative structural, biophysical, and virological approaches, we will pursue two specific aims to (1) define the atomic interactions, affinity, and specificity of the HAstV capsid for FcRn, and (2) define the roles of FcRn and DPP4 for HAstV attachment, internalization, capsid structural changes, and genome release. Results obtained by this work will elucidate mechanisms of HAstV entry and provide a foundation for the design of vaccines and therapeutics to prevent and treat HAstV infections.