MicrobiologyBytes

Noroviruses (NoVs) are a major cause of epidemic acute gastroenteritis affecting millions of people worldwide. Infection by NoVs relies on recognition of human histo-blood group antigens (HBGAs) as ligands or receptors for attachment, an early infection event that most likely controls host susceptibility and resistance to NoVs. HBGAs are complex carbohydrates on red blood cells, mucosal epithelia, saliva, milk and other body fluids, which are highly polymorphic and are related to the ABO, secretor and Lewis families. The interaction between NoVs and HBGAs has been extensively studied since it was discovered in 2002. Early studies using variable in vitro binding assays to measure the binding of NoV-like particles (VLPs) with HBGAs revealed diverse binding patterns. Further studies in human volunteer challenge and outbreak investigations provided direct evidence on the linkage between host blood types and susceptibility to NoV infection and, therefore, implicated HBGAs as NoV receptors or co-receptors, although undefined results were also reported.

Recent structural and functional analysis of the HBGA binding interfaces of NoVs has significantly advanced our understanding of the complicated interaction between NoVs and human HBGAs. For the first time, crystal structures of the HBGA binding interfaces of representative NoVs in complex with different HBGAs precisely elucidated interactions between individual amino acids in the binding interfaces of NoVs with specific saccharides of HBGAs. This article summarizes these advancements, proposes a new model of NoV–HBGA interaction, and discusses the role of HBGAs in NoV evolution and the resulting impacts on epidemiology and classification of human NoVs.

Norovirus-host interaction: Multi-selections by human histo-blood group antigens. Trends Microbiol. Jun 24 2011
The discovery of human histo-blood group antigens (HBGAs) as receptors or ligands of noroviruses (NoVs) raises a question about the potential role of host factors in the evolution and diversity of NoVs. Recent structural analysis of selected strains in the two major genogroups of human NoVs (GI and GII) demonstrated highly conserved HBGA binding interfaces within the two groups but not between them, indicating convergent evolution of GI and GII NoVs. GI and GII NoVs are probably introduced to humans from different non-human hosts with the HBGAs as a common niche. Each genogroup has further diverged into multiple sub-lineages (genotypes) through selections by the polymorphic HBGAs of the hosts. An elucidation of such pathogen–host interaction, including determination of the phenotypes of NoV–HBGAs interaction for each genotype, is important in understanding the epidemiology, classification and disease control and prevention of NoVs. A model of this multi-selection of NoVs by HBGAs is proposed.

Tweet

Even if we have never succumbed to it, we are all familiar with the sickness caused by noroviruses due to high-profile media coverage of outbreaks in various closed communities, such as hospitals and cruise ships. In this article in Microbiology Today, Ian Goodfellow and David Brown ask, how extensive are noroviruses in our food chain and what can be done to prevent outbreaks in future?

In the catering industry, education of food handlers is key. Clear guidelines for good practice in food preparation need to be strictly adhered to and policed. Whilst it is generally accepted that there remains an ongoing risk from oysters, etc, since sewage contamination of estuarine waters is likely to continue and depuration is ineffective for viruses, the development of sensitive screening procedures for identifying contamination has the potential to reduce the risk. Further improvements in decontamination of contaminated food and environmental settings will undoubtedly aid in minimizing the effects of norovirus contamination and outbreaks. Until such times that vaccines and/or antivirals are available, as consumers, good hygiene and common sense are the most effective protection against norovirus infection, i.e. increased hand washing, as well as avoidance of shared food sources/ utensils and pre-prepared food during outbreaks.

Read More

Related:

• Pathogenesis of Noroviruses
• How Noroviruses cause repeated outbreaks of gastroenteritis
• Norovirus evasion of the immune system

Human noroviruses in the family Caliciviridae are a major cause of epidemic gastroenteritis. They are responsible for at least 95% of viral outbreaks and over 50% of all outbreaks worldwide. Transmission of these highly infectious plus-stranded RNA viruses occurs primarily through contaminated food or water, but also through person-to-person contact and exposure to fomites. Norovirus infections are typically acute and self-limited. However, disease can be much more severe and prolonged in infants, elderly, and immunocompromised individuals. Norovirus outbreaks frequently occur in semi-closed communities such as nursing homes, military settings, schools, hospitals, cruise ships, and disaster relief situations. Noroviruses are classified as Category B biodefense agents because they are highly contagious, extremely stable in the environment, resistant to common disinfectants, and associated with debilitating illness. The number of reported norovirus outbreaks has risen sharply since 2002 suggesting the emergence of more infectious strains. There has also been increased recognition that noroviruses are important causes of childhood hospitalization. Moreover, noroviruses have recently been associated with multiple clinical outcomes other than gastroenteritis. It is unclear whether these new observations are due to improved norovirus diagnostics or to the emergence of more virulent norovirus strains. Regardless, it is clear that human noroviruses cause considerable morbidity worldwide, have significant economic impact, and are clinically important emerging pathogens. Despite the impact of human norovirus-induced disease and the potential for emergence of highly virulent strains, the pathogenic features of infection are not well understood due to the lack of a cell culture system and previous lack of animal models. This review summarizes the current understanding of norovirus pathogenesis from the histological to the molecular level, including contributions from new model systems.

Pathogenesis of Noroviruses, Emerging RNA Viruses. Viruses 2010, 2(3), 748-781 doi:10.3390/v2030748

Related:

• Noroviruses
• How Noroviruses cause repeated outbreaks of gastroenteritis
• The primary immune sensor for noroviruses

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. There are currently no vaccines or antiviral treatments available to treat or prevent the >260 million gastroenteritis cases 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.

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. This review discusses the molecular and structural mechanisms that facilitate the persistence of noroviruses in human populations.

Viral shape-shifting: norovirus evasion of the human immune system. 2010 Nature Reviews Microbiology 8, 231-241 doi:10.1038/nrmicro2296

Related:

• MicrobiologyBytes: Noroviruses
• How Noroviruses cause repeated outbreaks of gastroenteritis
• Tobacco plants make norovirus vaccine

Noroviruses are the leading cause of viral gastroenteritis (stomach flu), the symptoms of which include nausea, vomiting, and diarrhoea. There is no treatment for infection with these highly contagious viruses. While most people recover within a few days, the very young and old may experience severe disease. Like influenza, large outbreaks (epidemics) of Norovirus infection occur periodically (often in closed communities such as cruise ships), and most people have several Norovirus infections during their lifetime. Currently, many people are being infected each week in England with a new GII.4 variant. There are several reasons for this pattern of infection and reinfection. First, the immune response induced by a Norovirus infection is short-lived in some people, but not all. Second, there are many different noroviruses. Based on their genomes, noroviruses belong to five genogroups, which are further subdivided into genotypes. An immune response to one Norovirus provides little protection against noroviruses of other genogroups or genotypes. Third, like influenza viruses, noroviruses frequently acquire small changes in their genome. This process is called antigenic drift. Norovirus epidemics occur when virus variants emerge to which the human population has no immunity.

It is unknown exactly how noroviruses change over time or how they persist in human populations. In addition, little is known about susceptibility to Norovirus infections except that secretor-positive individuals people who express histoblood group antigens (HBGA) on the cells that line their mouths and guts are more susceptible than secretor-negative people, who express these antigens only on red blood cells. Information of this sort is needed to devise effective intervention strategies, therapies, and vaccines to reduce the illness and economic costs associated with norovirus outbreaks. In this study, the researchers investigate the molecular mechanisms governing the emergence and persistence of epidemic norovirus strains in human populations by analyzing how GII.4 Norovirus strains (the genotype usually associated with epidemics) have changed over time.

These findings suggest that the part of the Norovirus capsid protein that binds to sugars on host cells is under heavy immune selection and evolves over time by antigenic drift. They show that, like influenza viruses, GII.4 viruses evolve through serial changes in the capsid sequence that occur sporadically after periods of stability, probably to evade the build up of immunity within the human population. Variation in this region of the viral genome is possible because human populations express a great variety of HBGA molecules so there is always likely to be a subpopulation of people that is susceptible to the altered virus. Overall, these findings suggest that it should be possible to develop vaccines to protect against Norovirus infections but, just as with influenza virus, surveillance systems will have to monitor how the virus is changing and vaccines will need to be reformulated frequently to provide effective protection against Norovirus outbreaks.

Mechanisms of GII.4 Norovirus Persistence in Human Populations. PLoS Medicine 5, 2, e31
Our data suggest that the surface-exposed carbohydrate ligand binding domain in the Norovirus capsid is under heavy immune selection and likely evolves by antigenic drift in the face of human herd immunity. Variation in the capsid carbohydrate-binding domain is tolerated because of the large repertoire of similar, yet distinct HBGA carbohydrate receptors available on mucosal surfaces that could interface with the remodeled architecture of the capsid ligand-binding pocket. The continuing evolution of new replacement strains suggests that, as with influenza viruses, vaccines could be targeted that protect against Norovirus infections, and that continued epidemiologic surveillance and reformulations of Norovirus vaccines will be essential in the control of future outbreaks.

Hardly a day goes by without another outbreak of Norovirus infection being reported in the news. That’s particularly true at this time of year, and it’s no accident that the consequences of Norovirus infection used to be known as “winter vomiting disease”, although infections occur year round. And yet, in spite of how common they are, these viruses are not household names in the same way as influenza and polio, so MicrobiologyBytes comes to the rescue!

Subscribe to podcasts (free):
[iTunes] Enhanced podcasts
[RSS] mp3 podcasts (audio only)
Download this podcast (free):
Enhanced version
mp3 version (audio only)

Historically, noroviruses have been named after the places where outbreaks occurred. By far the most famous Norovirus is Norwalk virus, named after an outbreak of acute gastroenteritis in children at an elementary school in Norwalk, Ohio, in November 1968. These viruses remained poorly understood however, since for the most part, they do not grow in the laboratory. The taxonomy of these viruses became confused and they were previously grouped on the basis of their appearance in the electron microscope, and this led to the name “Small Round-Structured Viruses”. By adding labelled antibodies and performing immune electron microscopy (IEM), it became possible to be a bit more specific which virus was being studied. However, it was not until the genomes of these viruses were cloned and sequenced in the 1990s that the situation became clearer. Based on this molecular information, Norwalk virus and its troublesome little friends became a new genus, Norovirus, in the Calicivirus family, with which they share similarities.

Noroviruses are the most commonly identified cause of infectious gastroenteritis in Western Europe. They account for at least 10% of all gastroenteritis outbreaks in Europe, and an estimated 23 million cases in the USA each year (Lopman et al. Two Epidemiologic Patterns of Norovirus Outbreaks: Surveillance in England and Wales, 1992-2000. Emerging Infectious Diseases 9: January 2003). Noroviruses are responsible for more than 85% of all non-bacterial outbreaks of gastroenteritis (Hutson AM, et al. Norovirus disease: changing epidemiology and host susceptibility factors. Trends in Microbiol. 2004 12: 279-287). Only the common cold is reported more frequently than viral gastroenteritis as a cause of illness in the USA.

The symptoms of Norovirus illness usually include nausea, vomiting, diarrhoea, and stomach cramps. Sometimes patients may also have a low-grade fever, chills, headaches and muscle aches. The illness usually begins suddenly, and the infected person feels very sick. In most healthy people the illness is self-limiting with symptoms lasting for about a few days days. In general, children experience more vomiting than adults. There are usually no long-term health effects related to this illness. However, people who are are unable to drink enough liquids to replace the liquids they lost because of vomiting and diarrhoea can become dehydrated and may need special medical attention. This can be a particular problem in tropical climates, but also in the very young, the elderly, and persons with weakened immune systems.

Norovirus particles are excreted in large quantities in the stool or vomit of infected people. This means that the virus can spread rapidly in closed environments such as hospitals, nursing homes, schools and cruise ships. Hospital ward closures due to Norovirus outbreaks are a significant problem. Infection occurs when people eat food or drink liquids that are contaminated with the virus. Fruits, vegetables and shellfish contaminated with sewage are a common way for an outbreak to start, after which the virus can spread directly when people touch surfaces or objects contaminated with the virus, then place their fingers in their mouth. Norovirus outbreaks are fought with hygiene measures such as thorough and frequent handwashing, disinfection of contaminated surfaces and objects using a bleach-based household cleaner, washing clothing or linen that may be contaminated with virus after an episode of illness with hot water and detergent.

People infected with Norovirus are contagious from the moment they begin feeling ill (as soon as 12 hours after infection) to at least three days after recovery. Some people may be contagious for as long as two weeks after recovery, allowing “silent” spread of the virus. Currently, there is no antiviral medication that works against Norovirus and there is no vaccine to prevent infection. There is some evidence that blood types B and AB may confer partial protection against symptomatic Norovirus infections (Hutson AM, et al. Norwalk virus infection and disease is associated with ABO histo-blood group type. J Infect Dis 2002 185: 1335-1337).

It’s still not clear how many serotypes of Norovirus there are, or how protective infection with one virus is against another. However it is known that immunity is not permanent and reinfections do occur. One thing is sure, Noroviruses are not going away anytime soon, so unless we find out more about them, we might come to a sticky end!

• Caliciviruses
• Wikipedia: Noroviruses
• Estes MK, et al. Noroviruses everywhere: has something changed? Curr Opin Infect Dis. 2006 19: 467-74.