6gw0

Publication Abstract from PubMed

A recently developed human norovirus cell culture system revealed that the presence of bile enhanced or was an essential requirement for the growth of certain genotypes. Before this discovery, histo-blood group antigens (HBGAs) were the only well-studied co-factor known for human noroviruses and there was evidence that several genotypes poorly bound HBGAs. Therefore, the purpose of this study was to investigate how human norovirus capsid interact with bile acids. We found that bile acids had low micromolar affinities to GII.1, GII.10, and GII.19 capsids, but did not bind GI.1, GII.3, GII.4, or GII.17. We showed that bile acid bound at a partially conserved pocket on the norovirus capsid-protruding (P) domain using X-ray crystallography. An amino acid sequence alignment and structural analysis delivered an explanation of selective bile acid binding. Intriguingly, we discovered that binding of the bile acid was the critical step to stabilize several P domain loops that optimally placed an essential amino acid side chain (Asp375) to bind HBGAs in an otherwise HBGA non-binder (GII.1). Furthermore, bile acid enhanced HBGA binding for a known HBGA binder (GII.10). Altogether, these new data suggests that bile acid functions as a loop stabilizing regulator and enhancer of HBGA binding for certain norovirus genotypes.IMPORTANCE Given that human norovirus virions likely interact with bile acid during a natural infection and our evidence that an HBGA non-binder (GII.1) can be converted to an HBGA binder after bile acid binding is of major significance. Our data provides direct evidence that like HBGAs, bile acid interaction on the capsid is an important co-factor for certain genotypes. However, more unanswered questions seem to arise from these new discoveries. For example, is there an association between the bile acid requirement and prevalence of certain genotypes? That is, the GII.1 and GII.10 (bile acid binders) genotypes rarely caused outbreaks, whereas the GII.4 and GII.17 genotypes (bile acid non-binders) were responsible for large epidemics. Therefore, it seems plausible that certain genotypes require bile acids, whereas others have modified their bile acid requirements on the capsid.

Structural basis for human norovirus capsid binding to bile acids.,Kilic T, Koromyslova A, Hansman GS J Virol. 2018 Oct 24. pii: JVI.01581-18. doi: 10.1128/JVI.01581-18. PMID:30355683^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.