Abstract:In The Netherlands, illness due to Norwalk-like viruses (NLVs) of the family Caliciviridae is quite common. NLVs cause >80% of the outbreaks of gastroenteritis reported to municipal public health centers and at least 5% of the cases of gastroenteritis for which a general practitioner is consulted. In addition, up to 18% of community cases of gastroenteritis in the 1998/1999 winter season have been attributed to NLVs. Patterns of disease activity differ remarkably, with "normal years, when outbreaks occur that … Show more
“…Reverse line blot ( 38 ) was used in the Netherlands and Spain in 2000 and has since been adopted by a number of the other collaborating institutes to characterize Norovirus . The use of the heteroduplex mobility assay ( 37 ), reverse line blot ( 38 ), and sequencing to characterize virus has demonstrated the considerable and dynamic genetic diversity of human Caliciviridae ( 39 ). The use of such techniques by a wider group may demonstrate important differences in molecular epidemiology between countries and may detect the introduction of a novel strain to an area ( 40 ) by tracking and linking outbreaks over wide geographic areas.…”
To gain understanding of surveillance and epidemiology of viral gastroenteritis outbreaks in Europe, we compiled data from 10 surveillance systems in the Foodborne Viruses in Europe network. Established surveillance systems found
Norovirus
to be responsible for >85% (N=3,714) of all nonbacterial outbreaks of gastroenteritis reported from 1995 to 2000. However, the absolute number and population-based rates of viral gastroenteritis outbreaks differed markedly among European surveillance systems. A wide range of estimates of the importance of foodborne transmission were also found. We review these differences within the context of the sources of outbreak surveillance information, clinical definitions, and structures of the outbreak surveillance systems.
“…Reverse line blot ( 38 ) was used in the Netherlands and Spain in 2000 and has since been adopted by a number of the other collaborating institutes to characterize Norovirus . The use of the heteroduplex mobility assay ( 37 ), reverse line blot ( 38 ), and sequencing to characterize virus has demonstrated the considerable and dynamic genetic diversity of human Caliciviridae ( 39 ). The use of such techniques by a wider group may demonstrate important differences in molecular epidemiology between countries and may detect the introduction of a novel strain to an area ( 40 ) by tracking and linking outbreaks over wide geographic areas.…”
To gain understanding of surveillance and epidemiology of viral gastroenteritis outbreaks in Europe, we compiled data from 10 surveillance systems in the Foodborne Viruses in Europe network. Established surveillance systems found
Norovirus
to be responsible for >85% (N=3,714) of all nonbacterial outbreaks of gastroenteritis reported from 1995 to 2000. However, the absolute number and population-based rates of viral gastroenteritis outbreaks differed markedly among European surveillance systems. A wide range of estimates of the importance of foodborne transmission were also found. We review these differences within the context of the sources of outbreak surveillance information, clinical definitions, and structures of the outbreak surveillance systems.
“…In humans, norovirus infections occur worldwide and are responsible for as much as 94% of outbreaks of acute nonbacterial gastroenteritis [4][5][6][7]. The disease in humans is typically mild and self-limiting with symptoms of nausea, fever, vomiting, and diarrhea lasting for 24-48 h [7].…”
Murine noroviruses (MNV) comprise a group of newly recognized pathogens infecting laboratory mice. The first reported murine norovirus, murine norovirus 1 (MNV-1), produces a transient infection with a short duration of fecal shedding after infection of immunocompetent laboratory mice. Our laboratory subsequently isolated three novel murine noroviruses, murine norovirus 2 (MNV-2), murine norovirus 3 (MNV-3), and murine norovirus 4 (MNV-4), that have markedly different pathogenicity from MNV-1 by producing persistent infections and prolonged fecal shedding in infected immunocompetent mice. In this study, the nucleotide sequences and the predicted amino acid sequences of the three novel murine noroviruses were determined and compared to each other, MNV-1, and other previously described human and animal noroviruses. The three novel murine norovirus strains were shown to be related to each other and MNV-1 by sequence and phylogenetic analysis even though MNV-2, MNV-3 and MNV-4 all display markedly different biologic behavior from that of MNV-1.
“…Globally, NoV-associated deaths are estimated at 200,000 per year (3). Usually, disease severity is modest, but our awareness of morbidity and mortality rates, particularly among the young, elderly, and immunocompromised, is increasing (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). An effective vaccine would benefit not only these highly susceptible populations, but also military, child care, health care, and food industry personnel.…”
GII.4 noroviruses (NoVs) are the primary cause of epidemic viral acute gastroenteritis. One primary obstacle to successful NoV vaccination is the extensive degree of antigenic diversity among strains. The major capsid protein of GII.4 strains is evolving rapidly, resulting in the emergence of new strains with altered blockade epitopes. In addition to characterizing these evolving blockade epitopes, we have identified monoclonal antibodies (MAbs) that recognize a blockade epitope conserved across time-ordered GII.4 strains. Uniquely, the blockade potencies of MAbs that recognize the conserved GII.4 blockade epitope were temperature sensitive, suggesting that particle conformation may regulate functional access to conserved blockade non-surface-exposed epitopes. To map conformation-regulating motifs, we used bioinformatics tools to predict conserved motifs within the protruding domain of the capsid and designed mutant VLPs to test the impacts of substitutions in these motifs on antibody cross-GII.4 blockade. Charge substitutions at residues 310, 316, 484, and 493 impacted the blockade potential of cross-GII.4 blockade MAbs with minimal impact on the blockade of MAbs targeting other, separately evolving blockade epitopes. Specifically, residue 310 modulated antibody blockade temperature sensitivity in the tested strains. These data suggest access to the conserved GII.4 blockade antibody epitope is regulated by particle conformation, temperature, and amino acid residues positioned outside the antibody binding site. The regulating motif is under limited selective pressure by the host immune response and may provide a robust target for broadly reactive NoV therapeutics and protective vaccines.
IMPORTANCEIn this study, we explored the factors that govern norovirus (NoV) cross-strain antibody blockade. We found that access to the conserved GII.4 blockade epitope is regulated by temperature and distal residues outside the antibody binding site. These data are most consistent with a model of NoV particle conformation plasticity that regulates antibody binding to a distally conserved blockade epitope. Further, antibody "locking" of the particle into an epitope-accessible conformation prevents ligand binding, providing a potential target for broadly effective drugs. These observations open lines of inquiry into the mechanisms of human NoV entry and uncoating, fundamental biological questions that are currently unanswerable for these noncultivatable pathogens.
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