Norovirus and gastrointestinal disease The WritePass Journal

Norovirus and gastrointestinal disease Introduction Norovirus and gastrointestinal disease IntroductionVirologyClassificationStructureBiologyNorovirus Replication StrategyInfectivity of NorovirusEpidemiologyGeographic and Temporal DistributionTransmissionClinical featuresPathogenesisPrevention and controlRecent knowledge on contamination, sanitation and personal hygieneTreatmentHealth impact of Norovirus outbreaks in the coming eraReferencesRelated Introduction Norovirus is currently recognized as the most important non-bacterial pathogen causing gastroenteritis. It is believed that majority of gastroenteritis that occur throughout the globe is attributed to Norovirus. Norovirus was first recognised through immunoelectron microscopy (IEM) in 1972. However, it is only over the past decade that Norovirus has been of great interest to the basic scientists, virologists, epidemiologists and public health experts. There is no doubt that outbreaks or epidemics of Norovirus in the coming years will challenge the medical community to the limit. Globalisation has created a single, very mobile mega-population of people on earth in which more viruses can thrive, and, a highly infectious illness caused by Norovirus can spread rapidly, thus creating epidemics or even pandemics. The potential breakthrough in the development of Norovirus vaccine with the development of effective antigenic viral-like particles (VLP), and the recognition that Norovirus evolv es with antigenic drift will pose exciting challenges to all stakeholders. The other challenges or obstacles which we face include understanding the pathogenesis of the Norovirus in the gastrointestinal tract and identifying the site in the gastrointestinal tract which the virus replicates. This knowledge will hopefully allow the development of targeted antiviral therapy and thus prevent manifestation of severe clinical symptoms. This is a review of this very exciting, virus and I have chosen to amalgamate the current literatures into the following topics: Virology- Classification and structure Biology- Replication and infectivity Epidemiology- Geographic and temporal distribution Transmission Clinical features Pathogenesis Immunity Prevention and control Recent knowledge on contamination/sanitation and personal hygiene Vaccine development Treatments- Current and future Health impact of Norovirus outbreaks in the coming era Virology Classification Although Norovirus was first viewed in 1972, it was not until 1990 when it was classified. Classification of Norovirus could finally be performed due to the successful cloning of the viral genome (1). Molecular cloning and characterisation of Norovirus genome allowed this virus to be classified as a member of Caliciviridae family and it is known as a Group B Biodefense Pathogen. Caliciviruses are small (27-40nm), non-enveloped, icosahedral particles with single-stranded RNA of positive polarity. The name calicivirus comes from the Latin word calyx, meaning â€Å"cup† or â€Å"goblet†, which describes the cup-shaped depression, as observed under electron microscopy. Although they share similar features to that of the picornaviruses, caliciviruses are distinguished from their counterpart by having a larger genome and having distinctive spikes on the surface. Another example of calicivirus is the Hepatitis E virus (2). Currently, there are a few serotypes of Norovirus whic h were successfully identified through immunoelectron microscopy (IEM) and enzyme-linked immunosorbent essay (ELISA), which are represented by Norwalk virus (NV), Hawaii virus (HV), Snow Mountain agent (SMA), Desert Shield virus (DSV) and Southampton virus. (1). Currently, there are five main genogroups of Norovirus being identified (GI, GII, GIII, GIV and GV). Noroviruses, which can be found in humans, are from three genogroups (GI, GII and GIV). However, those that are commonly isolated in cases of acute gastroenteritis in humans belong only to two genogroups (GI and GII), which can then be further divided into genetic cluster or genotypes (i.e GI.1, GII.15, GIV.2 etc). There are now, at least 25 genotypes of Norovirus which were successfully identified, with the prototype Norwalk virus being labelled as GI.1 (Genogroup I, genotype 1) (3) and present within this genotype are numerous subtypes. The presence of this diversity of Norovirus strains are mainly due to both the accumulation of point mutations associated with error-prone RNA replication and to recombination between two related viruses (4, 5).   Genogroup I (GI) includes76 Norwalk virus, Desert Shield virus and Southampton virus and Genogroup II (GII), includes Bristol virus, Lor dsdale virus, Toronto virus, Mexico virus, Hawaii virus and Snow Mountain virus. Norwalk virus (NV), Snow Mountain virus (SMV), and Hawaii virus (HV) are the prototype strains of genotypes GI.1, GII.2, and GII.1 and are the causative agents of an estimated 5%, 8%, and 7% of Norovirus outbreaks, respectively (6). Genogroups III and V (GIII and GV) have only been identified in animals. Structure Through structural studies and visualisation of Norovirus by electron microscopy, it is now proven   that the Norovirus is composed of 90 dimers of the major capsid protein VP1 and one or two copies of the minor structural protein VP2 (7) which recognizes the histo-blood group antigens, which are regarded as receptors and host-susceptibility factors for infection (3). Figure 1. Structure of Norwalk Virus and Genome Non-enveloped, T=3 icosahedral symmetry, about 23-40 nm in diameter. Each virus particle is composed of 180 molecules of VP1 proteins which form 90-arch-like capsomers at all the local and strict twofold axes surrounding the hollows. The proteins in the capsid then folds into two main domains which are, the shell (S) domain and the protruding (P) domain, which contains two further subdomains, P1 and P2. The protruding, P domain functions to increase the stability of the capsid by increasing the intermolecular contacts between the dimeric subunits, thus, leading to speculation that it may control the size of the capsid. However, the S domain contains all the necessary protein requirements to initiate the assembly of the capsid (8). Norovirus has single stranded RNA genome and is predicted to contain three open reading frames (ORF) (9). The Norovirus genome is linear and contains approximately 7600 nucleotides (nt) (Southampton virus-7708nt, Lordsdale virus- 7555nt) (10).   The ORF1 (a polyprotein that contains sequence of amino acid which shows much similarity to that of Picornaviruses) is predicted to encode the capsid protein. ORF1 may be cleaved by 3CL proteases into 6 proteins (11). ORF2 and ORF3 are not shown in the diagram. However, until now, it is not known whether these ORF would be translated or what the function of its translated protein would be. In a recent study, Norovirus- like particles was viewed under atomic force microscopy. Scientist exposed the Norovirus-like particles in environments with PH ranging from 2 to 10. This range of pH values represents the pH of the natural environment in which Norovirus thrives. The study revealed that the Norovirus-like particles were resistant to indentation of measure of 300 bar at acidic and neutral pH. However, when the Norovirus-like particles were subjected to same indentation at a pH of 10, the capsid failed to regenerate and was irreversibly destroyed (12). All these studies which are still at an early stage will pave the way for further understanding of Norovirus. Biology Norovirus Replication Strategy Progress on understanding the basic mechanisms of virus replication has been far slower due to the inability to cultivate virus in the laboratory. Therefore, the replication strategy of this virus remains speculative and is presumed that its replication cycle is of a similar manner to that of picornaviruses (2).   As in the picornaviruses, the viral particle will bind to the cell surface receptors. This will result in a conformational change in the viral capsid proteins, and thus, releasing myristic acid (a common saturated fatty acid). This acid then helps in forming a pore in the cell membrane of the host cell and through this tiny hole; the RNA of the virus is injected (101). Once inside the cell, the RNA unwinds and the positive strand RNA genome is replicated through a double-stranded RNA intermediate which is formed using viral RDRP (RNA-Dependent RNA polymerase). Translation by host cell ribosomes is not initiated by the usual 5 G cap; instead it is initiated by IRES (Intern al Ribosome Entry Site). The viral replication cycle is short and it takes approximately 8 hours to complete one cycle of replication. Within 30 minutes after initial infection, cell protein synthesis – essentially the macromolecular synthesis of cell is â€Å"shut off†. Over the next one to two hours there is a loss of margination of chromatin and homogeneity in the nucleus. This is followed by synthesis of the viral proteins. Subsequently, a vacuole appears in the cytoplasm close to the nucleus and this vacuole gradually starts to coalace covering the whole cell. After 3 hour time, the cell plasma membrane becomes permeable and at 4–6 hours the virus particles assemble, and occasionally could be seen in the cytoplasm. At about 8 hours, the dead cell lyses and releases the viral particles (101). Infectivity of Norovirus Studies of the stability and hardiness of Norovirus have been done by experimental infection on humans. As Norovirus is the most important cause of food and waterborne disease, it is not unexpected that it is resistant to inactivation by treatment with chlorine concentrations which is usually used in drinking water (1). Norovirus can retain its infectivity   even after:- i) exposure to pH2.7 for 3 hours at room temperature, ii) treatment with 20% ether at 4 °C for 24 hours, or iii) incubation at 60 °C for 30 min (13). Norovirus can also retain infectivity after freezing (14). Recent reports have shown that through current sensitive antigen detection methods, Norovirus excretion was detected in 90% of ill volunteers. Viral shedding peaks 1-3 days after onset of symptoms, and studies have shown that the viral antigen may be shed for up to 56 days. Shedding of virus can occur in asymptomatic individuals and it can be prolonged in immunocompromised people. Also, antigen shedding can precede illness (15hr after infection and before symptomatic illness) (15). Epidemiology The successful cloning and expression of the Norovirus genome has led to the development of new assays which has allowed various epidemiological studies to be performed. Recent epidemiological studies have indicated that the infection with Norovirus is much more widespread than previously recognised (16). Geographic and Temporal Distribution Norovirus is highly infectious and can be spread easily from one person to another and is the leading cause of epidemic gastroenteritis in both the developed and developing countries. However, this epidemic gastroenteritis is usually mild, thus, differentiating it from infantile gastroenteritis (which is mainly caused by Rotavirus), which is a much more severe, and often life threatening diarrheal illness in infants and young children. Incidence of infection by Norovirus has been detected in all continents, and therefore, it has a global distribution. It has been quoted that in the United States, more than 90% of the outbreaks of gastroenteritis in the community, for which the cause was previously unknown, can now be attributed to Norovirus (2). Infection by Norovirus do occur all year round, however, its incidence is markedly increased during cold weather months (17).   Outbreaks typically occur in group settings such as cruise ships, schools, camps hospitals and nursing home wher e people gather in confined areas (2) and target a number of high risk populations, particularly young children and the elderly, travellers, soldiers and immunocompromised patients or those who are recipient of organ transplant. Every year, up to 1 million people in the UK are thought to be infected by Norovirus (18). If the Norovirus is brought into the hospital environment by someone incubating the infection, then it can easily spread to vulnerable hospital patients and also to staff. It is known to cause large outbreaks of infection in hospital which results in a lot of patients and staff being affected leading to closure of wards in order to prevent further spread. This has posed a huge problem on care provision. Hospitals, therefore, have very strict policies in place to control the spread of Norovirus which will be discussed later. Transmission Humans are believed to be the only host of the human Norovirus. Norovirus is transmitted mainly by the fecal-oral route. However, it can also be transmitted through infected vomitus (3) and there is currently increasing evidence that it can be transmitted through airbourne or fomite transmission (19 20). The infection of Norovirus is enhanced by several features which facilitate their spread. First, it has a low infection dose (approximately 18 to 1000 viral particles) (21) which allow the virus to spread through droplets, person-to-person contact and through environmental contamination. Secondly, excretion of virus in stools continued for several weeks even after recovery, thus, increases the risk of secondary spread which is a particular concern among food handlers and family members (22). Thirdly, the virus is resistant to a wide range of temperatures, chemicals and pH. The virus is able to persist on environmental surfaces and contaminated objects eg   in swimming pools, conta minated drinking water, ice, bakery products and also in raw oysters, fruits and vegetables which are eaten uncooked and cold foods (celery, melon, vermicelli, sandwiches and cold cooked ham) (3). Fourthly, due to the fact that there is a great diversity of Norovirus strains and the lack of long term immunity, it can result in occurrence of repeated infection throughout life. Finally, the Norovirus genome can also undergo mutations, which causes antigenic shift and recombination, which result in evolution of new strains of Norovirus which are capable of infecting hosts. Asymptomatic infections do occur, and such person may be the carriers of some outbreaks. In recent time, there is an increased in outbreaks in military camps and with the elderly who are staying in nursing or shelter homes, and also in hospital settings (19 20). These infections can be catastrophic because of high secondary attack rates, and such outbreaks can last for several months (18). Clinical features An unresolved problem related to transmission of Norovirus is how long an affected individual can stay infectious. Firstly, the incubation period of the virus is 10-51 hours. The main symptoms are sudden onset of vomiting (more common in children) and abdominal cramps (in 37-45% of the cases) followed by watery diarrhoea (more common in adults). The stools usually do not contain any blood or mucus and asymptomatic infection do occur in approximately 1/3 of the population. The duration of symptomatic illness lasts between 1-3 days (28-60 hr) but can last longer (4-6 days) in nosocomial outbreaks (3) and among children younger than 11 years of age (22). In 15% of patients, it lasts longer than 3 days. The illness also lasts longer in immunocompromised patients and in people with chronic illnesses (3). In immunocompetent adults, the course of Norovirus infection is rapid, with an incubation period of 24–48 hours and resolution of symptoms within 12–72 hours (23). The infec tion is usually less severe compared to other diarrheal infection. However, it can lead to dehydration and requires hospitalization, especially among children with an age of 5 yrs and adults, 65 yrs. Fatalities have been reported in relation to outbreaks of gastroenteritis among the elderly in nursing homes (24) and in the United Kingdom, there is an estimate of about 80 deaths from Norovirus every year among people who are older than 64 years of age (25). However, there are usually no long term effects of Norovirus infection and majority of patients recovers fully. Pathogenesis Because of the failure to cultivate the Norovirus in laboratory properly, our knowledge regarding the pathogenesis of Norovirus come mainly from physical, histological and biochemical studies on infected volunteers who took part in surveys. Proximal intestinal biopsy specimens were taken from ill volunteers and histological changes were compared to healthy individuals. Ill volunteers showed broadening and blunting of intestinal villi, crypt cell hyperplasia, cytoplasmic vacuolization and infiltration of polymorphonuclear and mononuclear cells into the lamina propria but the mucosa itself remaining intact. No histological changes were seen in the gastric fundus or in antrum or colonic mucosa (26). The extent of small intestine involvement remains unknown because studies have only examined the proximal small intestine, and the site of replication of the virus has yet to be identified. Studies have shown that small intestinal brush border enzymatic activity (alkaline phosphatase, sucras e and trehalase) were reduced, resulting to steatorrhea (lipids in stools) and transient carbohydrate malabsorption (27). Jejunal adenylate cyclase activity was not elevated (28) and changes in gastric secretion of hydrochloric acid (HCL), pepsin and intrinsic factor have been linked to these histological changes. In addition, gastric emptying was delayed and the reduced gastric motility may result in nausea and vomiting associated with this gastroenteritis. The binding specificity of Norovirus is based on the histo-blood group antigens. These histo-blood group antigens are complex carbohydrates (oligosaccharides) linked to proteins or lipids and are located on the mucosal epithelial of the digestive tracts and are present as free oligosaccharides in saliva and milk (29). The three major families of histo-blood group antigens- ABO, Lewis and secretor families- are involved in the binding of Norovirus (29). Different Norovirus genotypes have different affinity for ABO antigens. For example, GI Norovirus has a higher affinity for blood group antigens A and O whereas GII Norovirus has a higher affinity for blood group antigens A and B (30). The P2 domain on the viral capsid plays a key role in the binding of these Norovirus to the histo-blood group antigens (31). Prevention and control Outbreaks of Norovirus can result in loss of income and significant morbidity because of frequent secondary transmission of the disease. Places which are more prone to Norovirus outbreaks and are of particular concern are normally places with a closed environment such as hospitals, nursing homes, ships and planes. Because Norovirus is highly infectious and spreads easily, and can be spread via asymptomatic individuals, the prevention of Norovirus outbreaks has become a major obstacle and poses a challenge for us. Norovirus can begin with a single common source of contaminated food (i.e. raw oysters, fruits and vegetables) and can rapidly spread like wildfire through person-to-person contact. Stopping an outbreak of Norovirus requires herculean efforts to sterilise   and clean the environment (eg. on cruise ships, camp sites, nursing home, hospital wards or disaster sites), and even then, the epidemics will only subside once the viral pool have been totally eradicated (32,33). No specific methods are available for complete prevention of Norovirus infection or illness due the agent being extremely contagious. Therefore, control efforts are targeted and focused on identifying the source and the subsequent removal of that source (eg, an infected food handler, contaminated water supply or even contaminated food supply, which is often the case with fruits and shellfish- in particular, oysters) which will then reduce the chance of the virus spreading (34). It is advised that ill food handlers should not be able to retain to their job and that strict personal hygiene be enforced among food handlers as they are one of the main causes of outbreaks. However, even under these strict regulations, both measures have shown limited success. The key to stopping the continuous spread of outbreaks is by preventing the secondary spread of the virus which spread through person-to person contact and from contaminated environmental surfaces which normally occur in cruise ships and other institutions. The fact that asymptomatic infection can occur and that the antigen can still be shed 2-3 weeks after exposure need to be kept in mind to facilitate the managing of outbreaks. Methods to manage the outbreak of Norovirus infection will probably improve in the near future as new tests are being carried out in epidemiological research of virus transmission. Recent knowledge on contamination, sanitation and personal hygiene In an outbreak, whether in a hospital or other environment, various methods can be enforced to reduce the spread of Norovirus infection. It is also important to note that Norovirus gastroenteritis, which is highly contagious tend to spread in crowded areas and may be difficult to control, therefore, below, are just a few techniques which can help in controlling this spread. Proper hand washing techniques and washing hands with soap and water is the key to preventing Norovirus from spreading. Note that, alcohol hand gel does not kill the virus entirely, but it may still be useful in areas where water is inaccessible. Also, the efficacy of the alcohol based sanitizers depends on the alcohol type and concentrations as well as the amount of viral particles present (35). * Medical staff and aid workers should clean their hands prior to and after touching any patient but it is particularly important that staffs wash their hands with soap and water after attending to a Norovirus patient to prevent the infection from spreading from one patient to another patient via their hands. Staffs should also be educated about the importance of personal hygiene and about the importance of washing hands. * Visiting relatives of patients in hospitals should also wash their hands with soap and water after visiting a ward which has Norovirus and they should not interact with other patients other than the person they have come to visit. * Staff and visitors should wash their hands before handling food and after visiting the toilet. Hand washing facilities should also be provided especially in high risk areas which are prone to Norovirus infection, such as bathrooms, eating areas, diaper-changing areas and even day care centres. * Proper hand washing techniques (eg. Rub palm to palm with fingers interlaced and rub back of each hand with palm of the other hand with fingers interlaced) should also be advised and encouraged. * Strict personal hygiene among food handlers and aid workers should be enforced to prevent outbreaks of Norovirus. 2.  Ã‚  Ã‚   Isolating patients with the virus. *Patients with Norovirus must immediately be isolated from non-infected patient until their symptoms subside. The infected patient should be placed in a single room, but if there are a few cases of infection on the ward, infected patients should then be nursed in a dedicated bay. If there are a large number of cases, the ward should be close to new admissions. Visiting should also be restricted to prevent visitors getting the infection and thus, preventing the subsequent secondary infection of the disease. 3.  Ã‚  Ã‚   Cleaning. *Enhanced cleaning using bleach-containing products are needed to eradicate Norovirus from the environment. Vomit and diarrhoea must be cleaned up immediately and general ward cleaning must be increased. Alcohol based surface disinfectants are usually insufficient. Waste should also be dumped properly in the allocated bins. *Aggressive environmental sanitization by cleaning with proper surface disinfectants and sterilisation of bathroom surfaces, bedding and lines are also essential to decrease secondary spread (32). * Studies have shown that when bleaching agent is used on feline caliciviruses, it can inactivate the activity of the virus. Also, the effect of the bleaching agent is superior compared to that of ammonium compounds or phenols (36). 4.  Ã‚  Ã‚   Symptomatic people must stay away from hospital. *Staff and visitors who develop symptoms must not come into the hospital and they must remain away from the hospital until they have been free of symptoms for 48-72 hours. Staff must be cleared by occupational health before returning to work. Immunity and Vaccine Developed To develop future vaccines for the prevention of Norovirus infection, the nature of the immunity to Norovirus is of particular importance. In an early study of immunity of the human response system to Norovirus illness, some volunteers who became ill after being exposed to the virus had partial immunity to the disease upon exposure 6 to 14 weeks later, but lost the immunity 27 to 42 months later (37). However, recent studies have shown that these early finding may be inaccurate, since the dose required to infect 50% of volunteers is as low as 18 infectious particles, whereas the dose used in the early study was more than 105 time higher (21). Immunity developed from exposure to a lower dose of Norovirus might be greater and more cross-reactive than immunity against a much higher dose. Therefore, studies on this possibility are still on going. The high incidence of illness caused by Norovirus infections especially among both the young and the elderly have led to some investigations to consider the potential role of vaccines in helping to regulate this infection. The vaccine should be designated towards specific target groups, such as infants (as part of their routine schedule for childhood immunization), the elderly, food handlers, military personnel, travellers, health care workers and nurses in day-care centres (3). The development of vaccines could also play a role in helping to reduce the number of childhood mortality and controlling diarrheal disease in infants. In a recent study, it is noted that 15% of hospitalization of children for diarrhoea in India and 31% in Peru were associated with Norovirus infection (38) and these percentages may be contributing greatly towards the estimated 1.6 million children who die each year from diarrhoea. Nevertheless, recent breakthrough in research has successfully produced Norovir us-like particles (NVLP). These particles have almost identical characteristics to the original Norovirus as it has resistant properties towards acidic pH and is also heat-stable. When these particles are given orally or intranasally to human, it can produce an antigenic effect, stimulating the production of anti-Norovirus antibodies (B and T cell responses) within the human body (39). Therefore, these particles are now being studied, hoping that it could be used as a platform and lead us to discovering a cure one day. However, there are many obstacles towards the development of a vaccine for Norovirus. Firstly, there is certainly a lack of understanding of the physiology of the virus due to the failure to cultivate them in laboratories. Thirdly, there is limited understanding on why individuals cannot develop long term immunity towards the virus. Furthermore, the virus can also withstand a wide range of temperatures and pH thus increasing their survivability. Also, the virus has multiple routes of transmission, and finally, the Norovirus strain is rapidly evolving and mutating, thus, posing a major challenge for us in developing a vaccine, which is much similar to the situation to that of the influenza viruses. Similar to that of the influenza virus, the Norovirus can accumulate point mutation in the outer capsid wall which may result in unique immunoglobulin binding sites (18). Therefore, this antigenic drift will result in the formation of new strains of Norovirus and will require the reformatio n of the vaccines annually (39). Epidemic surveillance using recent updated epidemiological data will allow the identification of predominant strains and identifying a reference vaccine strain each year, similar to the situation of that of the influenza virus (38). Studies on the testing of vaccines are still at an early stage and much work still has to be done. Treatment As discussed above, the symptoms caused by Norovirus are generally mild and self-limited and resolves itself. Currently, there is still no specific treatment for a Norovirus infection apart from letting the infection run its course. Individuals who come down with Norovirus illness do not necessarily need to visit a doctor. Instead, the individual should stay home, to prevent the illness from passing to other people in a community, take paracetamol when necessary to relieve any symptoms or fever and most importantly, oral rehydration, by drinking plenty of water to replace the fluid lost through diarrhoea and vomiting. If an individual is having problems to retain fluids, he/she should try to take in small sips more frequently to ensure one is rehydrated. Rehydration solution can also be consumed to restore all the salts and minerals which were lost during diarrhoea and vomiting. This rehydration solution normally comes in powder form which can then be added with water for drinking. F or individuals who are suffering from severe dehydration, immediate hospitalization is necessary. Fluids should then be given directly into the body by a naso-gastric tube or intravenously. Antimotility agents such as Loperamide may be useful in helping to regulate diarrhoea in individuals with severe symptoms. Opioids are also useful in regulation of diarrhoea by reducing peristalsis. Anti-emetics such as Chlorpromazine, Acepromazine and Metoclopramide may be useful in helping to control vomiting by inhibiting the D2, Dopamine receptors which are found on the chemical trigger zone of the brain. Individuals suffering from Norovirus illness are advised to consume a light diet of foods that are easily digested, such as soup, rice, pasta and bread, but babies should be given their normal feed throughout (102). It has been shown that interferon and ribavirin can effectively inhibit the replication of Norovirus in replicon-bearing cells (40), but their potential therapeutic value needs t o be further investigated. Currently, there are still no anti-viral medications to treat Norovirus. Future research to locate the site of the gastrointestinal tract where the virus replicates may result in development of more specific antiviral therapies targeting the viral replication process. The drugs stated above are only used to control symptoms of Norovirus infection. However, due to the continuous advancement of the field of medicine, all these may change, and once the virus can successfully be propagated in laboratories, studies on them can be conducted which may finally lead us to a cure for Norovirus. Health impact of Norovirus outbreaks in the coming era Norovirus would be with mankind for years to come and even though a vaccine is in the process of being developed, it will require a few more years for it to be perfected. In this era of globalisation, travelling has become a norm in our lives. Every year, it is estimated that approximately 1 billion people travel around the globe for various purposes. Travellers may include tourists, business people, soldiers, refugees, migrants etc. Therefore, from a virus perspective, there will be a linkage of people all around the world with plenty of susceptible individuals which can be infected. For example, through air travel, the virus can be passed on from one continent to another, within a couple of days, and this can result in a pandemic. Currently, travel industry has increased by leaps and bounds. Planned vacations are almost the norm for everyone. Travellers especially vacationers inflicted with Norovirus will almost certainly ruined their travelling plans. On cruise ships or other confined environments, outbreaks of Norovirus can literally bring all leisure activities to a standstill. As global warming continues to be abated, natural disasters like hurricanes, typhoon, and floods appear to be common events. Congregation of people in crowded relief centres, like what happened during the Katrina Hurricane disaster, will form fertile ground for Norovirus to spread. Failure to control the outbreaks will compound the calamites (disasters) and disrupt relief effort. Lastly, as the world is rapidly greying especially in the developed countries, many old aged people will be housed in nursing homes. These confined homes are again sitting duck for Norovirus to strike. As the morbidity and mortality of old people are much worse in Norovirus infection, outbreaks could prove disastrous to these cohorts of greying population. References Richman D D, Whitley RJ Hayden FG Clinical Virology. 2nd ed. Washington: ASM Press; 2002. Levinson W Medical Microbiology Immunology. 8th ed. United States: Lange; 2004. Roger, I. Glass, Umesh, D. Parashar and Mary, K. Estes. Norovirus Gastroenteritis. N Engl J Med 2009;361:1776-85. Nayak MK, Balasubramanian G, Sahoo GC, et al. Detection of a novel intergenogroup recombinant Norovirus from Kolkata, India. Virology 2008;377:117-23. Bull RA, Tanaka MM, White PA. Norovirus recombination. J Gen Virol. 2007;88:3347-59. Fankhauser RL, J. S. Noel, S. S. Monroe, T. Ando, and R. I. Glass. Molecular epidemiology of Norwalk-like viruses in outbreaks of gastroenteritis in the United States. J. Infect. Dis. 1998;178:1571-1578. Michele E. Hardy Norovirus protein structure and function. DOI 2006;10.1016. Bertolotti-Ciarlet A, White LJ, Chen R, Venkataram P and Estes MK. Structural Requirements for the assembly of Norwalk virus-like particles. J. Virol 2002;76:4044-55. Zheng D, Ando T, Frankhauser RL, Beard RS, Glass RI, Monroe SS. Norovirus classification and proposed strain nomenclature. J. Virol 2006;346:312-23. Dingle KE, Lambden PR, Caul EO, Clarke IN. Human enteric Calicivirdae: the complete genome sequence and expression of virus-like particles from a genetic group II small round structured virus. J. Gen. Virol. 1995;76:2349-55. Belliot G, Sosnovtsev SV, Mitra T, Hammer C, Garfield M, Green KY. In vitro proteolytic processing of the MD145 Norovirus ORF1 nonstructural polyprotein yields stable precursors and products similar to those detected in Calcivirus-infected cells. J. Virol. 2003; 77:10957-74. Cuellar JL, Meinhoevel F, Hoehne M, Donath E. Size and mechanical stability of norovirus capsids depend on pH: a nanoindentation study. J Gen Virol. 2010; 91:2499-56. Dolin, R., N. R. Blacklow, H. DuPont, R. F. Buscho, R. G. Wyatt, J. A. Kasel, R. Hornick, and R. M. Chanock. Biological properties of Norwalk agent of acute infectious nonbacterial Cannon RO, Poliner JR, Hirschhorn RB, Rodeheaver DC, Silverman PR, Brown EA, Talbot GH, Stine SE, Monroe SS, Dennis DT and Glass RI. A multistate outbreak of Norwalk virus gastroenteritis associated with consumption of commercial ice.   J. Infect Dis. 1991; 164:860-863. Graham DY, Jiang X, Tanaka T, Opekun AR, Madore HP, Estes MK. Norwalk virus infection of volunteers: new insights based on improves assays. J. Infect. Dis 1994; 170:34-43. Inouye SK, Yamashita SY, Yoshikawa M, Kato N, Okabe N. Surveillance of viral gastroenteritis in Japan: paediatric cases and outbreak incidents. J. Infect. Dis 2000;181:S270-74. Adler JL, and Zickl R. Winter vomiting disease. J. Infect. Dis. 1969;119:668-73. Nilsson M, Hedlund KO, Thorhagen M, et al. Evolution of human caliciviruses RNA in vivo: accumulation of mutations in the protruding P2 domain of the capsid leads to structural changes and possibly a new phenotype. J. VIrol 2003;77(24):13117-24. [PubMed:14645568] Caul EO. Small round structured viruses: airbourne transmission and hospital control. Lancet 1994; 343:1240-41. Chadwick PR, McCann R. Transmission of a small round structured virus by vomiting during a hospital outbreak of gastroenteritis. J. Hosp. Infect. 1994; 26:251-59. Teunis PF, Moe CL, Liu P, et al. Norwalk virus: how infectious is it? J Med Virol 2008;80:1468-76. Rockx B, De Wit M, Vennema H, et al. Natural History of human calicivirus infection: a prospective cohort study. Clinical Infect Dis 2002;35:246-53 Estes MK, Prasad BV, Atmar RL. Noroviruses everywhere: has something changed? Curr. Opin. Infect. Dis. 2006;19:467-474. Mattner F, Sohr D, Heim A, Gastmeier P, Vennema H, Koopmamns M. Risk groups for clinical complications of Norovirus infections: an outbreak investigation. Clin Microbiol Infect 2006;12:69-74. Harris JP, Edmunds WJ, Pebody R, Brown DW, Lopman BA. Deaths from Norovirus among the elderly, England and Wales. Emerg Infect Dis 2008; 14:1546-52. Levy AG, Widerlite L, Schwartz CJ, et al. Jejunal adenylate cyclase activity in human subjects during viral gastroenteritis. Gastroenterology 1976;70:321-5 Agus SG, Dolin R, Wyatt RG, Tousimis AJ, Northrup RS. Acute infectious nonbacterial gastroenteritis: intestinal histopathology: histologic and enzymatic alterations during illness produced by Norwalk agent in man. Ann Intern Med 1973;79:18-25.   Meeroff JC, Schreiber DS, Trier JS, Blacklow NR. Abnormal gastric motor function in viral gastroenteritis. Ann Intern Med 1980;92:370-3. Marionneau S, Ruvoen N, Le MoullacVaidye B, et al. Norwalk virus binds to histo-blood group antigens present on the gastroduodenal epithelial cells of secretor individuals. Gastroenterology 2002;122:1967-77. Tan M, Huang P, Meller J. Mutations within the P2 domain of Norovirus capsid affect binding to human histo-blood group antigens evendence for a binding pocket. J. Virol. 2003;23:12562-71. Harrington PR, Lindesmith L, Yount B, Moe CL and Baric RS. Binding of Norwalk virus-like particles to ABH histo-blood group antigens is blocked by antisera from infected human volunteers or experimentally vaccinated mice. J. Virol 2002;76(23):12335-43. Yee EL, Palacio H, Atmar RL, Shah U, Kilborn C, Faul M, Gavagan TE, Feigin RD, Versalovic J, Neil, FH, Panlilio AL, Miller M, Spahr J and Glass RI. Widespread outbreak of Norovirus Gastroenteritis among evacuees of Hurricane Katrina residing in a Large â€Å"Megalshelter† in Houston, Texas: lessons learned for prevention. C Dis Cont. 2007;44:1032-39.   Widdowson MA, Cramer EH, Hadley L, et al. Outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominating circulating strain of Norovirus- United States, 2002. J Infect Dis 2004;190:27-36. [Erratum, J Infect Dis 2004;190:2198.] Baert L, Uyttendaele M, Stals A, et al. Reported foodbourne outbreaks due to Noroviruses in Belgium: the link between food and patient investigations in an international context. Epidemiol Infect 2009;137:316-25. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol 2002;23:S3-40. Duizer E, Bijkerk P, Rockx B, De Groot A, Twisk F, Koopmans M. Inactivation of caliciviruses. Appl Environ Microbiol. 2004;70:4538-43. Parrino TA, Schreiber DS, Trier JS, Kapikian AZ, Blacklow NR. Clinical immunity in acute gastroenteritis caused by Norwalk agent. N Eng J Med 1977;297:86-9. Patel MM, Widdowson M-A, Glass RI, Akazawa K, Vinje J, Parashar UD. Systematic literature review of role of Noroviruses in sporadic gastroenteritis. Emerg Infect Dis 2008;14:1224-31 Kralovetz MH, Mason HS, Chen Q. Norwalk virus-like particles as vaccines. Expert Rev Vaccines. 2010;9(3):299-307. Chang KO, Geroge DW. Interferons and ribavirin effectively inhibit Norwalk virus replication in replicon-bearing cells. J Virol 2007;81:12111-8. Websites Richard H.Replication of Polio, Rhino and other Picornaviruses [Internet]. Available from: pathmicro.med.sc.edu/virol/polio.htm Treating norovirus infection [Internet]. Available from: nhs.uk/Conditions/Norovirus/Pages/Treatment.aspx