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  • Review Article
  • Published:

Viral shape-shifting: norovirus evasion of the human immune system

Nature Reviews Microbiology volume 8, pages 231–241 (2010)Cite this article

Subjects

Key Points

  • Noroviruses are a major cause of gastroenteritis, and there are currently no vaccines or antiviral treatments available to treat or prevent the >260 million gastroenteritis cases that are reported globally each year. Noroviruses have proven difficult to work with in the laboratory owing to the lack of cell culture systems and animal models, and therefore little is known about the pathogenesis caused by this virus, which has hampered the development of efficacious therapeutics.

  • The norovirus family contains two genogroups (GI and GII) that are most commonly associated with enteric disease in humans, and these genogroups contain more than 25 different genotypes that account for most human norovirus cases. However, outbreaks caused by the GII.4 genotype occur much more frequently than those caused by other genotypes in the GII genogroup, and GI outbreaks occur even less frequently. Although the majority of norovirus outbreaks are caused by the GII.4 genotype, the molecular and biological factors that regulate this disease burden are only partially understood.

  • The GII.4 genotype seems to operate in a similar fashion as influenza virus, whereby evolution of novel immune escape variants allows the virus to escape the predominant memory immune response. By contrast, the prototypic GI.1 noroviruses have remained relatively static over the same time period, evolving variants with identical histo-blood group antigen binding capabilities and similar antigenic properties. The molecular mechanisms governing differential evolution patterns remain a key mystery in the norovirus field.

  • Immunity against noroviruses has been difficult to assess owing to the complex effects of host pre-exposure histories and differential host susceptibility, which is correlated with blood group and secretor status. However, recent work has suggested that the GI and GII genogroups may use different mechanisms to escape immunological memory and that this is perhaps directly related to the plasticity of and complex evolutionary-related sequence information encoded in the P2 subdomain of the capsid protein.

  • The GII genogroup contains more amino acid sequence in the P2 subdomain, which may allow increased capsid plasticity and a tolerance for more amino acid variation or insertions and deletions. This would provide a larger repertoire of sequence targets for natural selection and adaptation to complex environmental selection processes, like herd immunity. By contrast, the GI genogroup contains less sequence information with more conserved, surface-exposed residues that are probably recognized by homologous antibodies as well as antibodies generated against heterologous GI strains. Thus, complex patterns of GI pre-exposure history, antibody cross reactivity and original antigenic sin may facilitate secondary infections of GI strains, whereas antigenic drift and receptor switching allow GII noroviruses, especially GII.4 viruses, to persist in human populations.

Abstract

Noroviruses are the most common cause of food-borne gastroenteritis worldwide, and explosive outbreaks frequently occur in community settings, where the virus can immobilize large numbers of infected individuals for 24–48 hours, making the development of effective vaccines and antiviral therapies a priority. However, several challenges have hampered therapeutic design, including: the limitations of cell culture and small-animal model systems; the complex effects of host pre-exposure histories; differential host susceptibility, which is correlated with blood group and secretor status; and the evolution of novel immune escape variants. In this Review, we discuss the molecular and structural mechanisms that facilitate the persistence of noroviruses in human populations.

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Figure 1: Genome organization and capsid structure.
Figure 2: Phylogenetics of the norovirus capsid protein.
Figure 3: Variation in noroviruses that infect humans.
Figure 4: Genogroup variation.
Figure 5: Model of GI versus GII evolution in human populations.

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Acknowledgements

This work was supported by a grant from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (grant AID56351).

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Authors and Affiliations

  1. Department of Epidemiology and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Eric F. Donaldson, Lisa C. Lindesmith, Anna D. LoBue & Ralph S. Baric

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  1. Eric F. Donaldson
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Correspondence to Ralph S. Baric.

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Glossary

Caliciviridae

A family of small (2740 nm), non-enveloped, icosahedral enteric viruses that infect a broad range of host species. These positive-sense, single-stranded RNA viruses obtained their name from the Latin word calix, meaning chalice, owing to the cup-shaped structures on the surface of intact capsids. Caliciviruses are divided into four genera: Norovirus, Sapovirus, Vesiviruses and Lagoviruses.

Virus-like particle

A non-infectious particle formed by viral structural proteins that recapitulates the virus structure without packaging the viral nucleic acid or proteins that are normally packaged by the virus.

Protective immunity

An acquired immune response sufficient to protect an individual from infection or reinfection by a pathogen. It can be induced by vaccination or by previous exposure to a particular pathogen.

Quasispecies

A cloud of genetically similar viral genotypes, some of which may contain a less fit phenotype that is capable of exploiting a new niche that is created by the neutralization of the predominant viral phenotype.

Herd immunity

Immunity that occurs in a population when enough individuals become immune to a particular pathogen to break the transmission chain of that pathogen, providing pseudo-protection to non-immune individuals.

Histo-blood group antigen

A member of the family of complex glycans that are expressed on the surfaces of red blood cells, gut and respiratory epithelia, and biological secretions in humans. Their expression is regulated by the fucosyltransferase genesFUT1, FUT2 and FUT3, which are polymorphic in human populations. Differential expression of these enzymes determines the moieties and modifications to these ligands that are expressed by different humans.

Secretor-positive

Pertaining to an individual who expresses the FUT1 ABO blood group antigens on the cells that line their mouths and guts and whose saliva contains the same antigens.

Non-secretor

Pertaining to an individual who does not express the FUT1 ABO blood group antigens on the cells that line their mouths and guts and therefore do not secrete them in the saliva.

Triangulation number

A measure that is used to describe the structure of the icosahedral viral capsid and that was first described by Caspar and Klug. The icosahedron itself has 20 equilateral triangular facets, each of which is divided into a number (T) of identical equilateral triangular subdivisions (or protein subunits), such that the capsid has 20T structure subunits.

Original antigenic sin

A host-mediated humoral or cellular immune response in which a memory response against a previously encountered pathogen is preferentially used against a new pathogen variant rather than another primary response being produced.

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Donaldson, E., Lindesmith, L., LoBue, A. et al. Viral shape-shifting: norovirus evasion of the human immune system. Nat Rev Microbiol 8, 231–241 (2010). https://doi.org/10.1038/nrmicro2296

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