key: cord-0035500-6fv8mjld
authors: Iturriza-Gómara, Miren; Gallimore, Chris I.; Gray, Jim
title: Gastroenteric Viruses
date: 2007
journal: Foodborne Diseases
DOI: 10.1007/978-1-59745-501-5_8
sha: c89d0d57ac50248fe52522167072e00fe44b917c
doc_id: 35500
cord_uid: 6fv8mjld

In recent years, viruses have been recognized increasingly as an important cause of foodborne infections. More than 160 enteric viruses are excreted in the feces of infected individuals, and some may also be present in the vomitus. Food and water are directly contaminated with fecal material, through the use of sewage sludge in agriculture, sewage pollution of shellfish culture beds, or may be contaminated by infected food-handlers.

RVs are members of the Reoviridae family, and are nonenveloped triple-layered viruses, which possess a segmented genome consisting of 11 dsRNA segments. By EM, particles are approx 75 nm in diameter with a wheel-like structure from which they derive their name.

RVs are classified into groups A-E based on the antigenic differences of the viral middle layer (25) . Group A RVs are the most common cause of human gastroenteritis, but groups B and C RVs also infect humans. Group A RVs are further classified into subgroups (SG) based on the immunological reactivities of the middle layer protein VP6, and into G and P types according to the diversity of the outer layer proteins VP7 (Glycoprotein) and VP4 (Protease-sensitive protein), respectively (25) . Four different SGs (I, II, I+II and nonI/nonII), 14 or 15 G types (G1-G15) and 20 P types (P [1] -P [20] ) have been identified to date among Group A RVs (25).

ASVs are members of the Astroviridae family. They are nonenveloped viruses with a genome of positive-sense ssRNA. By EM, they appear as spherical particles of 35-40 nm in diameter with the characteristic 5-6 pointed Star of David configuration which gives these viruses their name.

ASVs are classified into eight serotypes (26) based on the serological tests using type-specific antibodies. Phylogenetic analysis of sequences from a region of the ORF2 has shown that genotypes correlate serotypes (27) .

Human ADVs are members of the Adenoviridae family. They are nonenveloped icosahedral particles of 80 nm in diameter and possess a genome of dsDNA. ADVs are classified into six different subgroups or species (A-F) and within these subdivided into 51 distinct serotypes according to immunological, biochemical, and biological differences (28) . Among these, ADVs of subgroup F, serotypes 40 and 41 have been associated with gastroenteritis, and these are termed enteric or fastidious ADVs (29, 30) .

CoVs and ToVs are two genus within the Coronaviridae family. CoVs are enveloped particles of 120-160 nm in diameter with an internal icosahedral core of approx 65 nm in diameter and a helical nucleocapsid. They have large surface projections with stem and globular portions which give them their characteristic appearance from which their name derives (corona is the latin word for crown) (28). CoVs are classified into three genogroups, of which genogroups 1 and 2 have human CoVs representatives (229E in genogroup 1 and OC43 in genogroup 2), and the SARS CoVs which initially appeared not to belong to any of the three known genotypes may possibly be classified within genogroup 2 (31) .

ToVs differ morphologically from CoVs in that their nucleocapsid has a tubular appearance and the particles may be disk-, kidney-, or rod-like shaped. ToVs are grouped in a single genogroup, which contains bovine, equine, porcine, and human viruses (27) .

Picobirnaviruses are a new genus of the Birnaviridae family (28) . These are nonenveloped round viruses of 24-41 nm diameter with a bi-segmented dsRNA genome. Picobirnaviruses have been found in human and animal feces (12) (13) (14) (15) .

Aichi virus is a member of the Picornaviridae family, recently included in a separate genus, kobuvirus, which also includes a bovine virus (32, 33) . They are small nonenveloped viruses of 22-30 nm diameter with a genome of positive-sense ssRNA.

Small round viruses or parvo-like virus particles found in human feces (34, 35) are DNA viruses of approx 22 nm diameter.

Although EM has traditionally been used for the detection of enteric viruses in the feces of infected individuals, this is a labor-intensive and relatively insensitive method, as detection requires approx 10 6 /g virus particles in feces. This is a problem particularly for the detection of caliciviruses (Table 2 ). Immune EM, which increases sensitivity and allows virus characterization when type-specific antibodies are used, has also been used for the detection of enteric viruses. Serological methods have been developed for the detection of some of these viruses. Enzyme immunosorbent assays (EIA) and passive particle agglutination tests (PPAT), some of which are available commercially, provide sensitivity comparable to, or better than, EM for the detection of RVs, NVs, ASVs, and ADVs. More recently, molecular methods, reverse-transcription polymerase chain reaction (RT-PCR), PCR, or nucleic acid-based sequence amplification (NASBA) assays have been developed for the detection of enteric viruses. These methods provide improved sensitivity for the detection of all enteric viruses, but have had a major impact on the detection of human caliciviruses (Table 3) . Viruses do not replicate in food or water, and the concentration of virus particles in contaminated products is likely to be very small and not distributed homogeneously throughout the foodstuff. Testing for the presence of viruses in food, water, or environmental samples has only been possible since the development of very sensitive molecular methods, which include virus elution from the foodstuff, followed by concentration (36) efficient nucleic acid extraction methods for the removal of inhibitors of amplification. One frequent source of foodborne enteric virus infections is shellfish. The development of a method for dissecting the stomach and digestive diverticula of shellfish (37) followed by nucleic acid extraction and DNA amplification-based methods (37-41) allows reliable and sensitive detection of enteric viruses in contaminated shellfish.

EM has been used for first-line diagnosis of NVs and SVs in clinical samples (17, 42, 43) , however in recent years, EM has been replaced in many laboratories with in-house or commercial EIAs for the detection of NVs (44) (45) (46) . Molecular diagnosis using nucleicacid extraction and RT-PCR assays has been introduced into many laboratories for the detection of NVs and SVs (23, (47) (48) (49) (50) (51) . With the development of sensitive nested PCR assays, detection of NVs contamination of foodstuffs has recently been feasible. In particular the detection of NVs in oysters and other shellfish has been widely reported (40, (52) (53) (54) (55) (56) (57) . Some foods, including raspberries, are contaminated with NVs (58) . The detection of NVs in other foodstuffs is still in its developmental stage although a few studies have been undertaken (59-61).

Because the number of RVs particles that are excreted at the peak of infection may be as high as 10 12 /g in feces, diagnosis can be made using EM. EM will not however distinguish between RVs of different groups, and for this immune EM can be used. Most laboratories use EIA or PPAT, which use broadly reacting capture antibodies directed against epitopes of Group A RV VP6, for the routine diagnosis of RV infections. Commercially available assays have a sensitivity for detection comparable to EM, but are more prone to nonspecific reactions (reviewed in ref. [62] ). The use of RT-PCR for the detection and characterization of RVs provides increased sensitivity and specificity (62) (63) (64) . Molecular methods for the detection of RVs are not routinely used in diagnostic laboratories, but their increased sensitivity make them useful for detecting low viral loads in asymptomatic infections, virus in samples that have been collected late after the onset of symptoms, or virus in environmental or food and water samples (40, (65) (66) (67) (68) .

ASVs were first detected by EM (69, 70) . Initially, characterization of ASVs was carried out by immune EM, but the development of EIA and RT-PCR assays for the detection and typing of ASV has made the detection of ASV available to diagnostic laboratories (27, (71) (72) (73) . In addition to increased sensitivity, the RT-PCR, used in conjunction with DNA sequencing, provides genotyping data which are vital for molecular epidemiological studies, and could be used for outbreak tracking, whether foodborne or otherwise.

ADVs were first identified by EM in the feces of children with gastroenteritis (74). These viruses induced typical cytopathic effects in cell culture, but could not be passaged or typed (75) , for this reason, these viruses were designated fastidious ADVs. Later, the cell line 293 was shown to support the propagation of enteric ADVs, and permitted the development of neutralization assays (76) . This method is, however, time consuming and relatively insensitive, and most diagnostic laboratories have a number of rapid serological tests available (immunofluorescence, EIA, and PPAT assays) many with a sensitivity of detection comparable to EM (reviewed in [77] ). In recent years, broadly reactive PCR methods have been developed for detecting ADVs, and in conjunction with restriction endonuclease analysis provide a sensitive tool for ADV characterization (78) . PCRs which use primers specific to a region of the genome (the long-fiber gene), highly conserved between ADV 40 and 41 but significantly divergent between these and other human ADVs have also been developed for the specific detection of enteric ADVs (79).

EM is inappropriate for the detection and identification of these viruses in clinical samples. Aichi viruses cannot be differentiated from other enteroviruses excreted in feces. An enzyme-linked immunosorbent assay was developed for the detection of antibody responses to Aichi virus infection and RT-PCR assays have also been developed to detect the RNA genome of the virus in fecal and oyster samples (80, 81) .

Many novel gastroenteric viruses in humans were first discovered by EM including ToVs (82, 83) , CoVs (6), and small round viruses (34) . The picobirnaviruses were first detected using polyacrylamide gel electrophoresis (PAGE) of RNA derived from rat and human feces (15, 84) . Molecular methods for the detection of these viruses have been developed (85, 86) , although further studies are required.

Humans are the principal reservoir of many of the enteric viruses, and person-toperson spread is the major route of transmission. The members of many virus families infect animal species (Table 4) , although zoonotic transmission is rare (87) with the exception of RVs (88) . Evidence of interspecies transmission of RVs has been obtained through comparative analysis of the genes derived from RV isolates from humans or animals either by whole-genome hybridization methods (89) or by gene sequencing and phylogenetic analysis (reviewed in ref. [90] ), and many RV genotypes are shared among different species (Table 5) .

The recent SARS epidemic is thought to have originated through transmission of the SARS CoV from an animal reservoir (91) , highlighting the potential for CoVs to cross the species barrier.

The lack of evidence for other viruses crossing the species barrier and of recombination/ reassortment between animal and human pathogens needs to be addressed. Concomitant studies of disease in humans and animals in the same geographical locations are required.

Foods that are consumed raw or minimally processed, such as fruit, vegetables, and shellfish, are typically implicated as vehicles for the transmission of enteric viruses. However, a wide variety of foods have been implicated in foodborne viral gastroenteritis outbreaks (Table 6) .

Enteric viruses can be present in foodstuffs through direct contamination with untreated sewage-sludge used in agriculture or sewage polluting shellfish culture beds. Food can also become contaminated during processing either by the use of polluted water in the preparation process or by infected food-handlers. Food-handlers have been shown to contaminate food during presymptomatic, symptomatic, and postsymptomatic infections (92-96). The majority of food-or waterborne outbreaks in which a virus is identified are caused by NVs (58, (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) . RVs, and possibly ASVs, have also been implicated in food-or waterborne outbreaks (5, 105, 106) , but much less frequently. Aichi virus was first isolated in 1989 in BS-C1 cells from patients in outbreaks of oyster-associated gastroenteritis, in Japan (16) . Later studies have also showed a link between oyster-associated gastroenteritis and the acquisition of Aichi virus-specific antibodies in some patients (110) .

SVs and ADVs have yet to be confirmed as the cause of any food-or waterborne gastroenteritis outbreaks. Recently, outbreaks suspected of being foodborne have been detected among passengers on cruise ships. Multiple enteric viruses, SVs, ADVs, NVs, and RVs were detected in symptomatic patients suggesting the ingestion of fecally contaminated food or water (unpublished data).

Gastroenteritis viruses infect mainly the epithelial cells of the proximal part of the small intestine. The intestinal lumen is lined with a layer of polarized epithelial cells (enterocytes), which cover the villi and crypts. The enterocytes lining the villi are nondividing absorptive cells, and those lining the crypts are undifferentiated proliferative cells that differentiate in order to renew the absorptive enterocytes of the villi. Some enteric viruses, RVs, ADVs, and ASVs infect the mature enterocytes exclusively, CoVs and ToVs infect the crypt and basal villus enterocytes, and enteric parvoviruses infect the crypt cells in the animal models (reviewed in [109] ). Viral diarrhea is caused by several factors:

• Primary malabsorption that originates from decreased absorption due to mature enterocyte cell death, which results in shortening of the villi, and also induces loss of enzymes leading to the accumulation of undigested carbohydrates and proteins. • Reactive crypt hyperplasia which leads to increased secretion into the intestinal lumen.

• Decreased intestinal motility induced by the autonomous central nervous system.

In RV diarrhea, the symptoms precede the appearance of any histological changes (112) . This suggested that, in RV infection at least, other mechanisms in addition to the Calves P [6] Pigs P [9] Cats P [11] Calves, horses P [14] Pigs P [19] Pigs ones described above must exist. One of the RV nonstructural proteins (NSP4), and a short peptide derived from it (aa 114-135) were shown to induce diarrhea in a dose-dependent manner in the neonatal mouse model (113) . NSP4 is the first identified viral enterotoxin, which has the capacity to mobilize intracellular calcium and increase the cellular membrane chloride permeability (114, 115) , and NSP4 is also secreted from the infected enterocytes in early infection (116) . Recently, it has been observed that RV evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system (117).

The incubation period for NVs is 24-48 h, and the mean duration of illness is 12-60 h. The clinical manifestations of NV are characterized by nausea, projectile vomiting, diarrhea, and abdominal cramps. Fever, chills, and lethargy can also occur (29) . Vomiting is usually more common in children, and diarrhea is the main symptom in adults (118, 119) . The incubation period for SVs is 24-36 h, with illness lasting for 1-4 d. Symptoms include diarrhea (95% cases) and vomiting (60%), as well as fever and abdominal pain (120).

The incubation period is usually 2 d, with the illness lasting for an average of 3-8 d (29) . Vomiting and watery diarrhea are the predominant symptoms, and fever and abdominal pain are also frequent. Extraintestinal spread of RVs has also been reported on numerous occasions, and may be associated to neurological disease (121, 122) .

The incubation period is between 24 and 36 h, with illness lasting for 1-4 d. Symptoms include vomiting, diarrhea, fever, and abdominal pain (29).

The incubation period can vary between 3 and 10 d, with illness often lasting for more than 1 wk. Diarhea is more prominent than vomiting or fever (29).

With Aichi virus gastroenteritis, diarrhea has been demonstrated in 58% of patients, and others include abdominal pain (92%), vomiting (71%), and fever (58%) (81) . However, these viruses have not been identified as a cause of gastroenteritis outside Japan, and their importance and spread remain unclear.

Viral gastroenteritis is usually self-limiting and its symptoms resolve without significant sequelae. In the cases of prolonged diarrhea, especially in infantile RV gastroenteritis, rehydration therapy with oral rehydration salt (ORS) solution (WHO formula; http://www.who.int/medicines/organization/par/edl/expcom13/ors.doc) or in severe cases, intravenous rehydration is indicated.

Enteric viruses are transmitted mainly from person-to-person. However, as these viruses are excreted in the feces of infected individuals, food and water can become contaminated with fecal material directly (sewage pollution) or indirectly by infected food-handlers.

The transmission of foodborne enteric virus infection by food-handlers can be prevented through the instigation of good hygiene practices. Symptomatic food-handlers should remain away from work for 48 h after the last episode of vomiting or diarrhea and should not prepare food for others during this period.

Procedures should be in place to address an incident of vomiting in the workplace. Exposed food and food that has been handled by an infected person should be destroyed. All contaminated areas, including vertical surfaces, must be thoroughly cleaned and attention to hand-washing procedures should be emphasized.

The extent of foodborne infection is not fully known (123, 124) , a study conducted in Sweden estimated the annual incidence of foodborne illness at 38-79 per 1000 inhabitants (125) . More alarming estimates from the United States attribute 76 million illnesses, 325,000 hospitalizations, and 5000 deaths to foodborne infections (126) . Mead To date, most foodborne viral gastroenteritis outbreaks have been associated with NV infections. However, it is likely that the other enteric viruses will also be transmitted via contaminated food and water with similar frequencies. A study assessing viral contamination of several shellfish beds in France that lasted more than 3 yr detected ASV in 17% of the samples, NV in 23%, enterovirus in 19%, and RV in 27% (40) . Similarly, in another study ADV contaminated shellfish was found in 47% of the samples tested and included sampling in areas considered unpolluted according to current methods for the determination of microbiological quality based on coliform counts (127) .

There may be several confounding factors that affect the detection of foodborne viral gastroenteritis. They include:

• Many laboratories will only investigate for the presence of NVs in suspected foodborne outbreaks. • NVs are an extremely diverse group of viruses (128) , and although several broadly reactive NV-specific assays are available, there is no single test that will detect all NVs with the same efficiency. Also, geographical differences detected among NV genotypes have been observed (unpublished data). Contaminated foodstuffs can be sourced from all over the world, and it is possible that the methods available in any one country, although being suitable for the locally endemic strains, may not be efficient for the detection of variants from other geographical regions. • Immunity to NV is short-lived (~6 mo) and the number of individuals susceptible to symptomatic illness is constantly high. However, other enteric viruses (RV, ADV, and ASV) induce long-lasting immunity, which does not prevent reinfections but protects most adults from illness. Therefore, identifying a foodborne outbreaks caused by RV or ADV may be difficult as most people will not show symptoms or these will be very mild, and may not even give rise to the suspicion of a foodborne outbreak.

It is clear that further work is required in order to properly estimate the burden of foodand waterborne viral diseases. The advent of molecular methods of exquisite sensitivity provides the tools for the examination of food and water and may provide data on the zoonotic transmission of animal viruses into the human population via the food chain.

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