Abstract
Noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. The calicivirus capsid is composed of 180 copies of VP1 with a molecular weight of ~58 kDa. This coat protein is divided into the N-terminus (N), the 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. Reviewed here are studies on murine norovirus (MNV) showing that the capsid responds to several physiologically relevant cues; bile, pH, Mg2+, and Ca2+. In the initial site of infection, the intestinal tract, high bile and metal concentrations and low pH cause two significant conformational changes: (1) the P domain contracts onto the shell domain and (2) several conformational changes within the P domain lead to enhanced receptor binding while blocking antibody neutralization. In contrast, the pH is neutral, and the concentrations of bile and metals are low in the serum. Under these conditions, the loops at the tip of the P domain are in the open conformation with the P domain floating on a linker or tether above the shell. This conformational state favors antibody binding but reduces interactions with the receptor. In this way, MNV uses metabolites and environmental cues in the intestine to optimize cellular attachment and escape antibody binding but presents a wholly different structure to the immune system in the serum. To our knowledge, this is the first example of a virus shapeshifting in this manner to escape the immune response.
Highlights
There are 11 genera in the Caliciviridae family of which seven infect animals including noroviruses
murine norovirus (MNV) can be propagated in a cell culture system, pathogenesis and the host immune response can be examined in the murine model, large amounts of virus can be readily produced, neutralizing monoclonal antibodies have been isolated, and an infectious clone has been developed [25]
It is interesting to note that all of the MNV monoclonal antibodies raised from infected mice that we have studied to date [12,26,31,33,34,36,37] clearly recognize the ‘open’ conformation at the apical loops observed in the apo structure at neutral pH
Summary
There are 11 genera in the Caliciviridae family of which seven infect animals including noroviruses. At low pH [20]Note and is that is the structure of MNV in with the presence of bile resting [11] or at [20]. Figure shows the entire capsid of of murine norovirus observed in the cryo-EM structures in the presence of bile and at low pH [20]. One copy of the capsid protein colored from blue to red as the chain extends from the amino to carboxyl termini. Conformation to which neutralizing of the P domain are loops splayed apart in an ‘open’ conformation to which neutralizing antibodies bind.This This changes the gut where high bile concentrations, low pH, and antibodies bind. The results reviewed here strongly suggest that MNV escapes the immune system by shapeshifting from a contracted structure in the gut that is primed for infection to an open structure in the serum that elicits the immune response
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
