Noroviruses

Abstract

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.

close

References

Atmar RL, Opekun AR, Gilger MA et al. (2008) Norwalk virus shedding after experimental human infection. Emerging Infectious Diseases 14(10): 1553–1557.

Bailey D, Thackray LB and Goodfellow IG (2008) A single amino acid substitution in the murine norovirus capsid protein is sufficient for attenuation in vivo. Journal of Virology 82(15): 7725–7728.

Bertolotti‐Ciarlet A, Crawford SE, Hutson AM and Estes MK (2003) The 3′ end of Norwalk virus mRNA contains determinants that regulate the expression and stability of the viral capsid protein VP1: a novel function for the VP2 protein. Journal of Virology 77(21): 11603–11615.

Bertolotti‐Ciarlet A, White LJ, Chen R, Prasad BV and Estes MK (2002) Structural requirements for the assembly of Norwalk virus‐like particles. Journal of Virology 76(8): 4044–4055.

Blakeney SJ, Cahill A and Reilly PA (2003) Processing of Norwalk virus nonstructural proteins by a 3C‐like cysteine proteinase. Virology 308(2): 216–224.

Burroughs JN and Brown F (1978) Presence of a covalently linked protein on calicivirus RNA. Journal of General Virology 41(2): 443–446.

Chang K‐O, Sosnovtsev SV, Belliot G, King AD and Green KY (2006) Stable expression of a Norwalk virus RNA replicon in a human hepatoma cell line. Virology 353(2): 463–473.

Chaudhry Y, Nayak A, Bordeleau M‐E et al. (2006) Caliciviruses differ in their functional requirements for eIF4F components. Journal of Biological Chemistry 281: 25315–25325.

Chaudhry Y, Skinner MA and Goodfellow IG (2007) Recovery of genetically defined murine norovirus in tissue culture by using a fowlpox virus expressing T7 RNA polymerase. Journal of General Virology 88(part 8): 2091–2100.

Cheetham S, Souza M, Meulia T et al. (2006) Pathogenesis of a genogroup II human norovirus in gnotobiotic pigs. Journal of Virology 80(21): 10372–10381.

Choi JM, Hutson AM, Estes MK and Prasad BV (2008) Atomic resolution structural characterization of recognition of histo‐blood group antigens by Norwalk virus. Proceedings of the National Academy of Sciences of the USA 105(27): 9175–9180.

Daughenbaugh KF, Fraser CS, Hershey JW and Hardy ME (2003) The genome‐linked protein VPg of the Norwalk virus binds eIF3, suggesting its role in translation initiation complex recruitment. EMBO Journal 22(11): 2852–2859.

Dolin R (2007) Noroviruses – challenges to control. New England Journal of Medicine 357(11): 1072–1073.

Duizer E, Schwab KJ, Neill FH et al. (2004) Laboratory efforts to cultivate noroviruses. Journal of General Virology 85(1): 79–87.

Ettayebi K and Hardy ME (2003) Norwalk virus nonstructural protein p48 forms a complex with the SNARE regulator VAP‐A and prevents cell surface expression of vesicular stomatitis virus G protein. Journal of Virology 77(21): 11790–11797.

Fankhauser RL, Noel JS, Monroe SS, Ando T and Glass RI (1998) Molecular epidemiology of “Norwalk‐like viruses” in outbreaks of gastroenteritis in the United States. Journal of Infectious Diseases 178(6): 1571–1578.

Farkas T, Nakajima S, Sugieda M et al. (2005) Seroprevalence of noroviruses in swine. Journal of Clinical Microbiology 43(2): 657–661.

Fernandez‐Vega V, Sosnovtsev SV, Belliot G et al. (2004) Norwalk virus N‐terminal nonstructural protein is associated with disassembly of the Golgi complex in transfected cells. Journal of Virology 78(9): 4827–4837.

Glass PJ, White LJ, Ball JM et al. (2000) Norwalk virus open reading frame 3 encodes a minor structural protein. Journal of Virology 74(14): 6581–6591.

Goodfellow I, Chaudhry Y, Gioldasi I et al. (2005) Calicivirus translation initiation requires an interaction between VPg and eIF4E. EMBO Reports 6(10): 968–972.

Guix S, Asanaka M, Katayama K et al. (2007) Norwalk virus RNA is infectious in mammalian cells. Journal of Virology 81(22): 12238–12248.

Herbert TP, Brierley I and Brown TD (1997) Identification of a protein linked to the genomic and subgenomic mRNAs of feline calicivirus and its role in translation. Journal of General Virology 78(part 5): 1033–1040.

Hsu CC, Riley LK, Wills HM and Livingston RS (2006) Persistent infection with and serologic cross‐reactivity of three novel murine noroviruses. Comparative Medicine 56(4): 247–251.

Kapikian AZ (2000) The discovery of the 27‐nm Norwalk virus: an historic perspective. Journal of Infectious Diseases 181(suppl. 2): S295–S302.

Karst SM, Wobus CE, Lay M, Davidson J and Virgin HWT (2003) STAT1‐dependent innate immunity to a Norwalk‐like virus. Science 299(5612): 1575–1578.

Katpally U, Wobus CE, Dryden K, Virgin HWT and Smith TJ (2008) The structure of antibody neutralized nurine norovirus and unexpected differences to virus like particles. Journal of Virology 82(5): 2079–2088.

Kuyumcu‐Martinez M, Belliot G, Sosnovtsev SV et al. (2004) Calicivirus 3C‐like proteinase inhibits cellular translation by cleavage of poly(A)‐binding protein. Journal of Virology 78(15): 8172–8182.

Lindesmith LC, Donaldson EF, Lobue AD et al. (2008) Mechanisms of GII.4 norovirus persistence in human populations. PLoS Medicine 5(2): e31.

Lopman B, Zambon M and Brown DW (2008) The evolution of norovirus, the “gastric flu”. PLoS Medicine 5(2): e42.

Lopman BA, Reacher MH, Vipond IB et al. (2004) Epidemiology and cost of nosocomial gastroenteritis, Avon, England, 2002–2003. Emerging Infectious Diseases 10(10): 1827–1834.

Meyers G (2003) Translation of the minor capsid protein of a calicivirus is initiated by a novel termination‐dependent reinitiation mechanism. Journal of Biological Chemistry 278(36): 34051–34060.

Mounts AW, Ando T, Koopmans M et al. (2000) Cold weather seasonality of gastroenteritis associated with Norwalk‐like viruses. Journal of Infectious Diseases 181(suppl. 2): S284–S287.

Muller B, Klemm U, Mas Marques A and Schreier E (2007) Genetic diversity and recombination of murine noroviruses in immunocompromised mice. Archives of Virology 152(9): 1709–1719.

Nilsson M, Hedlund KO, Thorhagen M et al. (2003) Evolution of human calicivirus RNA in vivo: accumulation of mutations in the protruding P2 domain of the capsid leads to structural changes and possibly a new phenotype. Journal of Virology 77(24): 13117–13124.

Pfister T and Wimmer E (2001) Polypeptide p41 of a Norwalk‐like virus is a nucleic acid‐independent nucleoside triphosphatase. Journal of Virology 75(4): 1611–1619.

Prasad BV, Hardy ME, Dokland T et al. (1999) X‐ray crystallographic structure of the Norwalk virus capsid. Science 286(5438): 287–290.

Rohayem J, Robel I, Jager K, Scheffler U and Rudolph W (2006) Protein‐primed and de novo initiation of RNA synthesis by norovirus 3Dpol. Journal of Virology 80(14): 7060–7069.

Scipioni A, Mauroy A, Vinje J and Thiry E (2008) Animal noroviruses. Veterinary Journal 178(1): 32–45.

Simmonds P, Karakasiliotis I, Bailey D et al. (2008) Bioinformatic and functional analysis of RNA secondary structure elements among different genera of human and animal caliciviruses. Nucleic Acids Research 36(8): 2530–2546.

Sosnovtsev SV, Belliot G, Chang K‐O, Onwudiwe O and Green KY (2005) Feline calicivirus VP2 is essential for the production of infectious virions. Journal of Virology 79(7): 4012–4024.

Sosnovtsev SV, Belliot G, Chang K‐OK et al. (2006) Cleavage map and proteolytic processing of the murine norovirus nonstructural polyprotein in infected cells. Journal of Virology 80(16): 7816–7831.

Straub TM, Bentrup KHZ, Orosz‐Coghlan P et al. (2007) In vitro cell culture infectivity assay for human noroviruses. Emerging Infectious Diseases 13(3): 396–403.

Thackray LB, Wobus CE, Chachu KA et al. (2007) Murine noroviruses comprising a single genogroup exhibit biological diversity despite limited sequence divergence. Journal of Virology 81(19): 10460–10473.

Tian P, Engelbrektson AL, Jiang X, Zhong W and Mandrell RE (2007) Norovirus recognizes histo‐blood group antigens on gastrointestinal cells of clams, mussels, and oysters: a possible mechanism of bioaccumulation. Journal of Food Protection 70(9): 2140–2147.

Willcocks MM, Carter MJ and Roberts LO (2004) Cleavage of eukaryotic initiation factor eIF4G and inhibition of host‐cell protein synthesis during feline calicivirus infection. Journal of General Virology 85(part 5): 1125–1130.

Wobus CE, Karst SM, Thackray LB et al. (2004) Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biology 2(12): e432.

Zheng DP, Ando T, Fankhauser RL et al. (2006) Norovirus classification and proposed strain nomenclature. Virology 346(2): 312–323.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bailey, Dalan, and Goodfellow, Ian(Mar 2009) Noroviruses. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000420]