Mouse Norovirus Uses Host Metabolites to Enhance Receptor Binding and Evade Immune Recognition

Noroviruses are the major cause of epidemic gastroenteritis in humans, causing ~20 million cases annually, resulting in more than 70,000 hospitalizations and 570-800 deaths in the United States alone. The T=3 icosahedral calicivirus capsid is composed of viral protein 1 (VP1) with three major domains: the N-terminus (N), shell (S), and C-terminal protruding (P) domains. The S domain forms a shell around the viral RNA genome, while the P domains dimerize to form protrusions on the capsid surface. The P domain is subdivided into P1 and P2 subdomains, with the latter containing the binding sites for cellular receptors and neutralizing antibodies. Mouse norovirus (MNV) is a widely used system for study of norovirus biology since we have a cell culture system, reverse genetic tools, and small animal model to eventually correlate structural information to whole animal pathology Mouse norovirus is a surprisingly dynamic virus that switches between receptor and antibody binding structures depending upon the in-vivo environment. In the circulation, the P domain floats above the shell by more than 15Å and the P domain loops (A’B’/E’F’) at the very tip are splayed apart in an ‘open’ conformation that antibodies learn to recognize. Upon ingestion, the low pH environment with high metal and bile salt concentrations in the alimentary canal each independently trigger the P domains to rotate 90° and contract by 15 Å onto the capsid surface. This hides any epitopes at base of the P domain. During this reversible collapse, the two P domains within the dimer rotate about each other and the A’B’/E’F’ loops adopt the ‘closed’ conformation. This opens the receptor binding site while burying the epitopes at the tip of the P domain. Therefore, rather than only depending on escape mutations to block antibody binding, MNV aggressively uses host conditions to remodel itself to enhance receptor binding while blocking antibody recognition. This review will describe the structural processes and biological consequences of the virus responding to activating host cues in the gut while these same triggers bury the epitopes presented in the circulation. This is an aggressive and unique mode of immune escape that has been subsequently shown in other viruses such as COVID-19. Therefore, a deeper understanding of the dynamic processes of virus capsids will improve vaccine design by understanding how to present the epitope conformations at the site of infection rather than what is presented to the immune system.