CHS Research Group Noroviruses

Noroviruses are the dominant cause of acute gastroenteritis around the world. Currently, there are no vaccines for noroviruses and cross-protection from future norovirus infections is uncertain, and it is not uncommon to be re-infected with a genetically similar strain. Although the disease is self-limiting, symptoms can persist for days or even weeks and transmission from person-to-person is difficult to control once the outbreak has occurred.

Noroviruses are an enormous problem in closed settings such as hospitals, nursing homes, cruise ships and schools. Human noroviruses are difficult to culture, but expression of the capsid protein in a baculovirus expression system results in the self-assembly of virus-like particles (VLPs) that are morphologically and antigenically similar to the native virion. The X-ray crystal structure of the VLP shows that the capsid is divided into two domains, shell and protruding (P) domains. The P domain is further divided into P1 and P2 subdomains, with the P1 subdomain interacting with the shell and the P2 subdomain residing on the outer surface of the capsid and likely containing the determinants for receptor binding and antigenicity.

Our research group is mainly focusing on the norovirus capsid using structural biology (X-ray crystallography and cryo-EM). We are interested in the structural basis for norovirus capsid binding to a known host factor (histo-blood group antigens - HBGAs), deciphering norovirus capsid flexibility (nanobodies and monoclonal antibodies), and discovering and developing norovirus antivirals against the capsid (fucose compounds, NIH clinical collection, and drug design).

This Junior Research Group is generously supported by the Chica and Heinz Schaller Foundation.

FUTURE OUTLOOK
Our group will continue studies on norovirus capsid interactions with the HBGAs using X-ray crystallography. The norovirus capsid is an ideal target for antiviral development. At present, the HBGA binding pocket is the only known site of host interaction, but other sites on the capsid are likely to be involved in host recognition. Indeed, we recently discovered another site on the capsid that is an ideal target for developing drugs (see ref. 1). We are now planning on testing several compounds in cell culture using murine norovirus as a model. We also plan to develop rapid diagnostic tests that can detect a broader range of norovirus strains in order to reduce the transmission of these viruses.