Some people are resistant to Norwalk virus (NV) infection; however, the factor(s) responsible for resistance or susceptibility to NV infection has not been identified. This study investigated the relationship between a person's ABO histo-blood group type and the risk of NV infection and symptomatic disease after clinical challenge. ABO phenotypes were identified by using serum samples from volunteers who participated in an NV challenge study (n=51). Individuals with an O phenotype were more likely to be infected with NV (odds ratio [OR], 11.8; 95% confidence interval [CI], 1.3-103), whereas persons with a B histo-blood group antigen had decreased risk of infection (OR, 0.096; 95% CI, 0.16-0.56) and symptomatic disease (OR, 0; 95% CI, 0-0.999). This is the first report demonstrating an association between a genetic factor and the risk of NV infection and symptomatic disease.

Members of Norovirus, a genus in the family Caliciviridae, are causative agents of epidemic diarrhea in humans. Susceptibility to several noroviruses is linked to human histo-blood type, and its determinant histo-blood group antigens (HBGAs) are regarded as receptors for these viruses. Specificity for these carbohydrates is strain-dependent. Norwalk virus (NV) is the prototype genogroup I norovirus that specifically recognizes A-and H-type HBGA, in contrast to genogroup II noroviruses that exhibit a more diverse HBGA binding pattern. To understand the structural basis for how HBGAs interact with the NV capsid protein, and how the specificity is achieved, we carried out x-ray crystallographic analysis of the capsid protein domain by itself and in complex with A-and H-type HBGA at a resolution of Ϸ1.4 Å. Despite differences in their carbohydrate sequence and linkage, both HBGAs bind to the same surface-exposed site in the capsid protein and project outward from the capsid surface, substantiating their possible role in initiating cell attachment. Precisely juxtaposed polar side chains that engage the sugar hydroxyls in a cooperative hydrogen bonding and a His/Trp pair involved in a cation-interaction contribute to selective and specific recognition of A-and H-type HBGAs. This unique binding epitope, confirmed by mutational analysis, is highly conserved, but only in the genogroup I noroviruses, suggesting that a mechanism by which noroviruses infect broader human populations is by evolving different sites with altered HBGA specificities.norovirus ͉ receptors ͉ x-ray crystallography ͉ cation-interaction

Background-Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy aVect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. Methods-We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotypephenotype correlations. Results-In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely aVected, while UPD and ID patients are the least. DiVerences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. Conclusions-Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15. (J Med Genet 2001;38:834-845)

Norwalk virus (NV) was first isolated from an outbreak of winter vomiting disease, or acute gastroenteritis, at an elementary school in Norwalk, Ohio, in 1968 (1). Subsequent adult volunteer challenge studies with infectious stool filtrate from the Norwalk outbreak demonstrated that NV readily infects susceptible people, causing an acute illness associated with diarrhea, vomiting, myalgia, nausea, and fever within 15 to 24 h after exposure and lasting 24 to 72 h (16). Although these initial studies demonstrated that most people are highly susceptible to NV, presently no cell culture systems or animal models of infection exist, which limits the study of NV replication and pathogenesis.NV is the prototype nonenveloped, positive-stranded RNA human virus in the genus Norovirus of the family Caliciviridae. Noroviruses are a major cause of acute gastroenteritis throughout the world and cause virtually all outbreaks of nonbacterial gastroenteritis in adults in the United States (18, 39). Furthermore, there are an increasing number of reports of gastroenteritis cases and outbreaks in children and the elderly caused by noroviruses, in part due to increased surveillance and better detection methods (15,26,39).NV virions are detected in low numbers in infected stool. The virions are 27 to 38 nm in diameter, including 4.5-nm radial protrusions extending from the capsid shell that create the calix, or cup-like structures, apparent by electron microscopy (33, 44). The NV capsid proteins (open reading frames 2 and 3, which produce the structural viral proteins VP1 and VP2, respectively) spontaneously self-assemble into virus-like particles (VLPs) when synthesized in a recombinant baculovirus expression system. These recombinant NV VLPs (rNV VLPs) are structurally and antigenically similar to the capsids of native NV and are useful in modeling virus-cell interactions (27, 53).Hemagglutination (HA) is one method that has been helpful in identifying cell-binding receptors for many viruses, such as influenza A virus and parvovirus B19 (7, 45). The VLPs from human parvovirus B19, JC human polyomavirus, and SA11 simian rotavirus have HA properties that are similar to those of their virions (8,14,42). This is the first report of HA by VLPs from a human calicivirus. Our data demonstrate that the H type 2 histo-blood group antigen is the rNV VLP HA receptor on human type O red blood cells (RBCs) and that the rNV VLPs also bind to synthetic H and structurally related Lewis carbohydrate antigens. MATERIALS AND METHODSrNV VLP purification. rNV VLPs were synthesized and purified by using methods described previously (53). Briefly, spinner flasks containing 3.5 ϫ 10 6 Sf9 insect cells per 200 ml of Grace's insect cell medium were infected with pVL-NV ORF(2 ϩ 3) recombinant baculovirus at a multiplicity of infection of 5. At 7 days postinfection the rNV VLPs were harvested from supernatants of spinner flask cultures. Cells were pelleted and discarded. The VLPs in the supernatant were pelleted by ultracentrifugation through a 30% sucrose cus...

Specific binding of virus to oysters can selectively concentrate a human pathogen.