Research Article: The Evolution of Norovirus, the “Gastric Flu”

Date Published: February 12, 2008

Publisher: Public Library of Science

Author(s): Ben Lopman, Maria Zambon, David W Brown

Abstract: The authors discuss the implications of a new study that presents compelling data to show that norovirus evolution is driven by immune selection pressure.

Partial Text: Linguistically speaking, the predominant viral cause of gastroenteritis has been evolving. Once evocatively called winter vomiting disease, the pathogen’s name has changed alongside improved scientific understanding. First called Norwalk virus (or Norwalk-like virus) in reference to the Ohio town where specimens from a school outbreak enabled the seminal work that first characterised the virus, it was later dubbed the Small Round Structured Virus following visualisation by electron microscopy. The International Committee on Taxonomy of Viruses later settled on the present name of “norovirus”, classifying it as a member of the Caliciviridae family based on both morphology and phylogeny. A new study published in this issue of PLoS Medicine suggests that the colloquial “gastric flu” may have been the most apt term of all [1]. When media reports call “norovirus” just “a fancy word for gastric flu”, they allude to similar seasonality and the lack of effective therapeutics for influenza and norovirus, but the analogy may run deeper [2]. There are parallels with respect to influenza and norovirus evolution and human immunity.

Noroviruses are the most commonly detected pathogen both in sporadic cases and outbreaks of gastroenteritis. They are particularly problematic in environments where groups congregate and infection can be rapidly transmitted through both faecal and vomitus routes. Outbreaks affect health care facilities worldwide, and may cause massive disruption to providing care, substantial economic loss, and, according to some reports, mortality in vulnerable patient populations [3–5]. As is typical of positive-sense single-stranded RNA viruses, noroviruses are diverse. There are two main genogroups affecting humans and approximately 15 genotypes within these groups, with substantial genetic heterogeneity between genogroups (60% divergence in the ORF2 major capsid protein) and genotypes within a genogroup (approximately 20%–30% divergence). At least since 1995 a single type—genotype II.4—has been the predominant circulating virus.

Some individuals, upon being challenged with norovirus infection, develop gastroenteritis, while others develop asymptomatic infection and some show no signs of infection at all. This points to a role of acquired immunity as well as innate resistance to infection. Indeed, individuals who genetically encode the enzyme FUT2 a-fucosyltransferase and are secretor-positive (i.e., they express HBGAs) are susceptible to Norwalk virus (a GI.1 virus) infection. Distinct binding patterns have been described for a range of other GI and GII strains, including GII.4. Acquired immunity is not thought to last until a subsequent norovirus season, though a few individuals may acquire longer-lasting immunity. With these factors combined, one might think that immune selection pressure would be rather transient—only heavy at the end of a season—and that an evolutionarily stable strategy for norovirus might be to wait out the summer low season and attack again when population immunity has waned. This is not what Baric and colleagues have found.

Instead, their findings suggest (1) that noroviruses are under heavy selective pressure and (2) that the norovirus capsid, which contains both antigenic sites and carbohydrate binding ligands, seems to have been finely tuned to evolve. The P2 region of the capsid is attached to the virus shell by a flexible hinge, so—with minor genetic tweaking—the virus can nuzzle up to a range of HBGA sites. This domain is evolving at a faster rate than regions not coding for surface residues.

Baric and colleagues’ landmark paper sets forth a wide research agenda for norovirus vaccinology, virology, and epidemiology. The authors are bullish that their findings take us towards the development of norovirus vaccines. This is undoubtedly true—though it is unlikely that a major pharmaceutical company will invest the massive sums required to bring to market a product for such an antigenically diverse virus that confers short-lived immunity and is perceived to cause a relatively low burden of disease. We think this lack of investment in developing a vaccine would be unfortunate; vaccination targeted at vulnerable populations and health care workers could mitigate the most severe health and economic consequences caused by noroviruses. Formulation of a norovirus vaccine would be challenging, but tools developed for understanding influenza evolution could prove useful. For example, data generated from Baric and colleagues’ serological experiments lend themselves to fascinating antigenic mapping methods used to quantify and visualise antigenic differences between circulating influenza strains [9], and may prove effective in predicting norovirus evolution.



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