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Noroviruses and Sapoviruses (Caliciviruses)
Reviewed for currency November, 2019
Acute infectious gastroenteritis is an exceedingly common and widespread illness throughout the world. Noroviruses are major causes of this illness, which is generally self-limited but can result in hospitalization, mortality in young children in the developing world, and severe illness in elderly and immunocompromised patients. Sapovirus, another calicivirus, and Astrovirus (see Chapter 177 ) also cause gastroenteritis but are much less common than noroviruses.
History
The failure to isolate causative agents, bacterial or viral, from apparently infectious outbreaks of diarrhea or vomiting, or both, led to the widely held assumption that undetected viruses were responsible for such disease. In 1945, Reimann and coworkers transmitted disease to volunteers by administering bacteria-free filtrates of throat washings, stool filtrates, or both from naturally occurring cases. Gordon and Jordan and their associates also induced disease in volunteers with bacteria-free material. These studies described two transmissible agents of subbacterial size, the Marcy and FS agents, which appeared to be antigenically distinct. However, these workers were unable to detect viral agents in vitro with techniques available at that time. Despite extensive virologic investigations in laboratories throughout the world, relatively little progress was made in this area until 1972, when the Norwalk virus, the prototype of this group, was described and partially characterized. This virus was initially detected in diarrheal stools obtained during an outbreak of gastroenteritis in Norwalk, Ohio, that involved students in an elementary school and family contacts. Subsequently, additional viruses with similar properties were described, including the Hawaii, Montgomery County (MC), Taunton, and Snow Mountain viruses, also named for the geographic regions in which they were first recognized. All these viruses had a similar small, round, structured morphologic appearance with electron microscopy; were of a similar size and density; did not grow in any in vitro propagation system; and were responsible for acute gastroenteritis, commonly in epidemic form with high secondary attack rates. At the same time, viruses with more readily identifiable morphologic features with electron microscopy, referred to as human caliciviruses, were observed in the stools of individuals, primarily children, with gastroenteritis.
A major advance in this field occurred when polymerase chain reaction (PCR) techniques were applied to amplify the genome of the Norwalk virus from virion-containing stool samples. These studies identified the Norwalk virus as a member of the Caliciviridae family and allowed determination of the complete nucleotide sequence of this virus. Subsequent molecular studies have clearly identified all these viruses as caliciviruses and established them as major causes of gastrointestinal disease in both adults and children worldwide.
Virology
Taxonomy
The name calicivirus, and hence the virus family Caliciviridae, is derived from the characteristic appearance of the viral particles on electron micrographs, which consists of a scalloped border with cuplike indentations on its surface ( Fig. 176.1 ), from which the Latin name chalice or calyx is derived. Caliciviruses have been detected in a variety of animal species, including marine mammals, swine, felines, and rabbits, in addition to humans. Five genera have been described: Norovirus, Sapovirus, Vesivirus, Lagovirus, and Nebovirus. Human infections are caused by Norovirus and Sapovirus . Vesivirus causes vesicular diseases in swine, cats, and marine mammals; Lagovirus causes hemorrhagic diseases in rabbits; and Nebovirus causes enteric disease in calves. The prototypical Norovirus is the Norwalk virus, and the prototypical Sapovirus is the Sapporo virus. In addition to sequence differences, the genera differ in minor details of genome organization. Whereas many animal caliciviruses replicate efficiently in cell culture, the propagation of human noroviruses or sapoviruses in vitro has been difficult to achieve, although transfection of viral RNA from norovirus in human embryonic cells and infection of human intestinal organ cultures have been reported. Thus, much of the initial microbiologic information on noroviruses was based on physical properties determined with electron microscopy or by means of physicochemical manipulation of infectious inocula. Because of the small numbers of virions characteristically found in stool samples, it is sometimes necessary to enhance electron microscopic visualization of the particles through the addition of immune serum, which obscures the typical morphologic features ( Fig. 176.2 ). Recently a major breakthrough was reported, in which efficient culture of human norovirus was achieved in enterocytes obtained from stem cells in human intestinal epithelium. The cultivation of noroviruses in vitro in a B-cell line has also been reported. These advances should enable efficient, detailed molecular characterization of noroviruses to be carried out, along with facilitation of efforts to develop effective vaccines and therapeutics (see later).
Genome Organization
Characteristics of the noroviruses include a single-stranded, positive-sense RNA genome with a polyadenylated 3′ tail and a single capsid polypeptide of 59- to 62-kDa molecular mass. The virions are 26 to 34 nm in diameter, have cubic symmetry with a buoyant density in cesium chloride of 1.34 to 1.41 g/mL, and are relatively heat and acid stable and ether resistant.
The genomic organization of noroviruses is shown in Fig. 176.3 . Noroviruses have a positive-sense, single-stranded RNA genome of approximately 7700 nucleotides, excluding the polyadenylated tail. Three long open reading frames (ORFs) are present. The first ORF encodes a polyprotein of about 57-kDa molecular weight, which includes and codes for seven nonstructural proteins, including the viral RNA polymerase, helicase, and protease functions. The second ORF encodes the viral capsid protein (VP1) of 58-kDa molecular weight, which determines the antigenic phenotype and interacts with host cell receptors. When expressed in eukaryotic cells, the capsid protein spontaneously assembles into virus-like particles (VLPs), which are immunogenic and react specifically with convalescent human sera. The three-dimensional structure of these empty capsids has been studied with electron cryomicroscopy, which suggests that the capsid has icosahedral symmetry with T = 3. The x-ray crystallographic structure of these VLPs shows that the capsid contains two domains, a shell (S) domain and a protruding (P) domain that may be involved in binding to susceptible cells. Finally, the third ORF encodes a minor structural protein (VP2) of 12- to 29-kDa molecular weight, which may add to particle stability and may also be involved in capsid assembly and genome encapsidation. The overall genetic organization of sapoviruses is similar to that of noroviruses, except that sapoviruses contain two ORFs. ORF-1 encodes both nonstructural and the major structural protein (VP1), whereas ORF-2 encodes the minor structural protein. A third ORF has been predicted in several sapoviruses, but its function is unknown.
Based on phylogenetic analyses, noroviruses have been subdivided into seven genogroups designated GI to GVII, and the genogroups have been further divided into at least 34 genotypes. Individual genotypes are designated by Arabic numerals after the genogroup designation—for example GI.1 or GII.1. Most of the strains implicated in human disease fall into genogroups GI and GII, but GIV strains also infect humans. The GI genogroup includes the Norwalk virus, whereas the Snow Mountain and Hawaii viruses belong to genogroup GII.
Sapoviruses have also been further subdivided into 14 genogroups (GI to GXIV), of which GI, GII, GIV, and GV are known to infect humans. Multiple genotypes within the genogroups have also been noted.
Antigenic Characterization
Because of the lack of a convenient in vitro propagation system, antigenic characterization of these viruses has not been straightforward until now. Not unexpectedly, predicted amino-acid homology within the capsid region is less than that within the polymerase region. Thus, phylogenetic trees based on capsid sequence have a slightly different structure than those based on polymerase structure. VLPs have been generated by expression of the capsid regions of many of the noroviruses, including Norwalk and Desert Shield viruses (genogroup GI) and MX, Lordsdale, Snow Mountain, Hawaii, and Toronto viruses (genogroup GII), in addition to the prototype sapovirus, Sapporo. In general, hyperimmune animal sera raised against capsids are very specific. However, tests of postinfection human sera have suggested a significant degree of cross-reactivity among viruses within a genogroup.
The most clear-cut antigenic distinction among noroviruses is between the Norwalk and Hawaii viruses because these agents have been compared through cross-challenge experiments in human subjects. In these studies, infection with the Norwalk virus provided short-term protection against rechallenge with the Norwalk virus but not against the Hawaii virus, and vice versa. Because this type of experiment is the closest analogue to virus neutralization that has been previously available, this is direct evidence that there are at least two distinct norovirus serotypes, roughly corresponding to the GI and GII genogroups described earlier.
Epidemiology
With the advent of efficient means for their detection (see later), noroviruses have emerged as major, worldwide causes of gastroenteritis in diverse populations and in both children and adults. Noroviruses are the most common cause of epidemic gastroenteritis and account for more than 90% of outbreaks of viral gastroenteritis and for about 50% of all-cause outbreaks worldwide. Noroviruses are also important causes of sporadic cases of gastroenteritis and account for 4.4% to 30.7% of children younger than 5 years who are hospitalized with gastroenteritis throughout the world. Overall, it has been estimated that noroviruses cause 699 million illnesses and 219,000 deaths annually worldwide. Mortality is believed to occur primarily in children younger than 5 years. The Centers for Disease Control and Prevention (CDC) estimates that noroviruses cause 40% to 50% of foodborne outbreaks of gastroenteritis in the United States and overall account for 21 million cases of gastroenteritis, 2 million office visits, 70,000 hospitalizations, and up to 800 deaths annually in the United States.
Antigenic Variation
The role of antigenic variation in the epidemiology of noroviruses remains an area of continued investigation. In general, antibody to noroviruses within genogroup II appears to be more common than to viruses within genogroup I. However, a number of diverse genotypes often cocirculate, including recombinants among different strains, and there may be year-to-year variation in the predominant viruses associated with illnesses. Despite this, viruses from a single genotype, GII.4, have been responsible for the majority of outbreaks worldwide since 1995. Novel pandemic GII.4 variants have evolved every 2 to 3 years since the 1990s and replaced previously predominant GII.4 strains. GII.4 strains were the predominant strains associated worldwide with outbreaks from 2001 to 2012. In 2014, GII.17 virus emerged and spread worldwide in 2014–2015.
The epidemiology of sapoviruses has been less extensively studied than that of noroviruses, but sapoviruses appear to be substantially less frequent causes of outbreaks of gastroenteritis than noroviruses. The original Sapporo virus was reported in Japan and appeared to affect young children primarily. Subsequently, sapoviruses have been reported in outbreaks in adults in various settings, including long-term care facilities. Reports have indicated that sapoviruses caused 1.8% to 8.0% of outbreaks that were studied in diverse geographic locales.
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