Noroviruses are one of the primary causes of acute gastroenteritis in man in the developed world, yet may also cause acute and persistent infections in animals. The study of noroviruses has been largely hindered by the lack of an efficient cell culture system for the viruses which infect humans. However, new advances in molecular techniques and the identification of animal noroviruses have led to a recent increase in our understanding of the structure and function of the virus, as well as the proteins encoded by the positiveā€stranded ribonucleic acid (RNA) genome. Our knowledge of the molecular mechanism of norovirus genome translation and replication lags behind that of many positiveā€stranded RNA viruses but recent studies have highlighted some unique and interesting features of these economically important pathogens.

Key Concepts:

  • The causative agent of norovirus disease is a small RNA virus.

  • The virus replicates in the gastrointestinal tract of its host.

  • Noroviruses infect a wide range of mammals, including humans where they represent a significant cause of viral gastroenteritis.

  • Noroviruses are highly transmissible and capable of causing serious epidemics.

  • Norovirus virions have icosahedral symmetry.

  • The norovirus genome is positive sense, meaning it is directly translated into proteins.

  • Norovirus genome replication is thought to occur through an antigenome intermediate.

  • The replication process takes place in the cytoplasm of infected cells.

  • Reverse genetics systems are available for some noroviruses allowing detailed investigation of their replication strategies and the molecular determinants of their pathogenicity.

Keywords: Norwalk virus; norovirus; calicivirus; gastric flu; gastroenteritis

Figure 1.

The Norovirus genus is one of four recognized genera of Caliciviruses. There are also two additional proposed genera (Recovirus (e.g. Tulane virus) found in rhesus macaques and Beco/Nabo‐virus (e.g. Newbury‐1) found in bovines). Noroviruses infect a wide range of mammals, a list that is continually expanding. Subclassification into genogroups (GI‐V) and multiple genotypes is based on partial genome sequencing (traditionally capsid and polymerase).

Figure 2.

Top panel: A VP1 dimer, as found in the ‘AB’ conformation in the capsid of Norwalk virus. The VP1 protein is divided into two regions, the shell (S) (green highlighted region) found on the internal surface of the icosahedral virion and the protruding (P) domain that extends outwards and is thought to mediate attachment and entry into the host cell. The P domain can be further subdivided into P1 (red) and P2 (blue). The P2 domain contains the binding pocket for HBGA (a) (approximate position labelled). For clarity, the other VP1 protein in the dimer has been left unshaded – the dimer–dimer interface indicating the region of interaction. Bottom panel: The norovirus capsid has icosahedral symmetry (simplified diagram shown) with 180 copies of the VP1 protein forming the complex 3D structure. The capsids of norovirus are thought to dimerize in two conformations (A/B – shown earlier and C/C – not shown). These alternative dimers then assemble at points of 5‐ (b) and 3‐ (c) fold symmetry to allow sufficient curvature to close the capsid structure. An approximate example of the A/B dimer interactions at the 5‐fold axis of symmetry (b) is shown. For simplicity the protruding domains have been removed from the crystal structures, and a top‐down view of 5 A/B dimer S domains is presented (again one half of the dimer has been left unshaded). Molecular graphics images were produced using the Chimera package from the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco (supported by NIH P41 RR‐01081). The norovirus capsid structure was downloaded from the open access Research Collaboratory for Structural Bioinformatics (RCSB) protein data bank (PDB file reference: 1ihm, Prasad et al., ).

Figure 3.

Norovirus genomes vary in length from approximately 7.3 to 7.7 kb (without the polyA tail) and are accompanied by a shorter but sequence‐analogous subgenomic (SG) RNA during infection (generated from the genomic (G) RNA). The genome normally contains three open reading frames (ORFs); however, MNV has an additional conserved internal open reading frame (ORF4) found in ORF2/VP1. Translation of G and SGRNA is mediated by the VPg protein that is linked to 5′ ends of both the genomic and subgenomic RNA. ORF1 is generated as a polyprotein and posttranslationally cleaved into the nonstructural proteins (NS1‐7) at the positions indicated. ORF2 and ORF3 (and ORF4 of MNV) are thought to be translated from the SGRNA template. The viral proteins have alternative nomenclature based on their genome position (e.g. NS1‐2), their size (e.g. p22) or their proposed picornavirus orthologues (e.g. 3A). These alternative names are also indicated. ORF1 and ORF2 are very close, sometimes overlapping in the genome, as do ORF2 and ORF3. The length of this overlap varies as does their mechanism of translation. ORF2 is thought to be translated conventionally from the SGRNA. ORF3 is thought to be translated by a novel stop–start mechanism of translation at the end of ORF2. ORF4 of MNV may be translated by leaky scanning and read‐through of the ORF2 AUG. Note that the genome is not drawn to scale.



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Further Reading

Estes MK, Prasad BV and Atmar RL (2006) Noroviruses everywhere: has something changed? Current Opinion in Infectious Diseases 19(5): 467–474.

Le Pendu J, Ruvoen‐Clouet N, Kindberg E and Svensson L (2006) Mendelian resistance to human norovirus infections. Seminars in Immunology 18(6): 375–386.

Marshall JA and Bruggink LD (2006) Laboratory diagnosis of norovirus. Clinical Laboratory 52(11–12): 571–581.

Teunis PF, Moe CL, Liu P et al. (2008) Norwalk virus: how infectious is it? Journal of Medical Virology 80(8): 1468–1476.

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Bailey, Dalan, and Goodfellow, Ian(Mar 2009) Noroviruses. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000420]