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Norovirus immunity and the great escape.

Debbink K, Lindesmith LC, Donaldson EF, Baric RS - PLoS Pathog. (2012)

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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Noroviruses (NoVs), members of the Calicivirus family, are small, positive-polarity RNA viruses and the most important cause of human foodborne viral gastroenteritis worldwide... Expression of most HBGAs on mucosal tissues is dependent on the presence of a functional FUT2 gene, which codes for a fucosyltransferase that adds side chains to a precursor molecule... About 20% of people do not encode a functional FUT2 gene and are considered “non-secretors” (Figure 1D)... Short-term immunity has previously been established for GI.1 viruses, and a recent vaccine study found that intranasal vaccination with GI.1 VLPs protected against disease three weeks post vaccination... The existence of long-term immunity is more controversial; however, multiple studies found protective responses against GI.1 were present six months after challenge in some but not all individuals, ,... GI and GII antibodies are high in acute sera, while cross-blockade patterns are genogroup-specific, ... Sera against GI outbreaks are cross-blocking within the genogroup and are sometimes higher for a heterologous strain after infection, ; however, the blocking response does not extend to GII NoVs... Importantly, New Orleans 2009 and its recent derivatives demonstrate continued evolution in the major blockade epitopes, suggesting escape from GII.4–2006 herd immunity... While multiple blockade epitopes change over time, conserved, unmapped GII.4 blockade epitopes also exist... No GI or cross-GI and GII antibody blockade epitopes have been mapped, signaling an important priority for future studies... To further characterize the complexity of the molecular mechanisms driving antigenic variation, additional crystal structures in complex with strain, genotype, and genogroup-specific antibodies are needed to define complete epitopes, tease apart overlapping epitopes, and map the exact residues comprising important cross-reactive and cross-blockade epitopes... Human NoV infection or vaccination elicits a primarily CD4+ Th1 response, leading to increased secretion of IFN-gamma and IL-2, ... One study using human-derived PBMCs found that T cell responses were more cross-reactive between GII strains with higher antigenic relatedness, while another study found that T cell responses toward alternate GI strains were more robust than the immunizing GI strain in some individuals... Areas of the capsid undergoing positive selection over time in rapidly evolving NoV genotypes will need to be continuously monitored in order to keep abreast of novel surface variation that may lead to escape from herd immunity and emergence of new pandemic strains... The potential effects a vaccine would have on the evolutionary dynamics of emerging NoV strains will need to be clarified.

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NoV Genetic Diversity, Structure, and Binding Ligand.1A:NoV genome schematic. The NoV genome encodes three open reading frames. ORF 1 encodes the nonstructural proteins (blue); ORF 2 encodes VP1, the major capsid protein (purple); and ORF 3 encodes VP2, the minor capsid protein (green). VP1 is further divided into the shell, which forms the base of the virion (teal); the P1 subdomain, which forms a stalk-like projection from the surface (orange); and the P2 subdomain, which is the most variable and surface-exposed area of the virion, contains ligand binding sites, and interacts with potentially neutralizing antibodies (red). 1B: NoV phylogenetic tree. NoVs are divided into five genogroups. Genogroups 1 (pink) and 2 (orange) cause the majority of human disease. Genogroups are further divided into genotypes. Genotype GII.4 NoVs (red bracket) account for ∼80% of outbreaks. Genotype GI.1 NoVs are the prototypic Norwalk viruses. 1C: NoV capsid protein (VP1) cryo EM image. Colors correspond approximately to the shell (teal), the P1 subdomain (yellow/orange) and the P2 subdomain (red). 1D. Secretor/non-secretor phenotype pathways. Enzymes (Secretor or Lewis) add specific modifications to a precursor molecule. Individuals without a functional FUT2 gene cannot express HBGAs from the left branch of the pathway (left of the dotted line) on mucosal surfaces. For those without a functional FUT2 gene (non-secretors), the precursor molecule can still be modified by the Lewis enzyme to make Lewis a antigen (branch on the right side of the dotted line).
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ppat-1002921-g001: NoV Genetic Diversity, Structure, and Binding Ligand.1A:NoV genome schematic. The NoV genome encodes three open reading frames. ORF 1 encodes the nonstructural proteins (blue); ORF 2 encodes VP1, the major capsid protein (purple); and ORF 3 encodes VP2, the minor capsid protein (green). VP1 is further divided into the shell, which forms the base of the virion (teal); the P1 subdomain, which forms a stalk-like projection from the surface (orange); and the P2 subdomain, which is the most variable and surface-exposed area of the virion, contains ligand binding sites, and interacts with potentially neutralizing antibodies (red). 1B: NoV phylogenetic tree. NoVs are divided into five genogroups. Genogroups 1 (pink) and 2 (orange) cause the majority of human disease. Genogroups are further divided into genotypes. Genotype GII.4 NoVs (red bracket) account for ∼80% of outbreaks. Genotype GI.1 NoVs are the prototypic Norwalk viruses. 1C: NoV capsid protein (VP1) cryo EM image. Colors correspond approximately to the shell (teal), the P1 subdomain (yellow/orange) and the P2 subdomain (red). 1D. Secretor/non-secretor phenotype pathways. Enzymes (Secretor or Lewis) add specific modifications to a precursor molecule. Individuals without a functional FUT2 gene cannot express HBGAs from the left branch of the pathway (left of the dotted line) on mucosal surfaces. For those without a functional FUT2 gene (non-secretors), the precursor molecule can still be modified by the Lewis enzyme to make Lewis a antigen (branch on the right side of the dotted line).

Mentions: NoVs are divided into five genogroups (GI-GV), which differ by >60% based on capsid sequence [3], and GI and GII NoVs cause the majority of human disease (Figure 1A–C). Genogroups are further divided into genotypes, which differ by about 40%, with GI.1 as the prototypic “Norwalk” genotype and the GII.4 NoVs as the genotype responsible for the majority (80%) of outbreaks [4]. GII.4 NoVs in particular appear to accommodate a high level of sequence diversity and undergo positive selection in key surface-exposed residues, likely allowing for escape from herd immunity [1], [5]. Differences in evolution rates among different GI and GII NoVs have been attributed to receptor switching and effective population size, VP1 sequence space and structural plasticity, duration of herd immunity, and replication fidelity [1], [6]–[9].


Norovirus immunity and the great escape.

Debbink K, Lindesmith LC, Donaldson EF, Baric RS - PLoS Pathog. (2012)

NoV Genetic Diversity, Structure, and Binding Ligand.1A:NoV genome schematic. The NoV genome encodes three open reading frames. ORF 1 encodes the nonstructural proteins (blue); ORF 2 encodes VP1, the major capsid protein (purple); and ORF 3 encodes VP2, the minor capsid protein (green). VP1 is further divided into the shell, which forms the base of the virion (teal); the P1 subdomain, which forms a stalk-like projection from the surface (orange); and the P2 subdomain, which is the most variable and surface-exposed area of the virion, contains ligand binding sites, and interacts with potentially neutralizing antibodies (red). 1B: NoV phylogenetic tree. NoVs are divided into five genogroups. Genogroups 1 (pink) and 2 (orange) cause the majority of human disease. Genogroups are further divided into genotypes. Genotype GII.4 NoVs (red bracket) account for ∼80% of outbreaks. Genotype GI.1 NoVs are the prototypic Norwalk viruses. 1C: NoV capsid protein (VP1) cryo EM image. Colors correspond approximately to the shell (teal), the P1 subdomain (yellow/orange) and the P2 subdomain (red). 1D. Secretor/non-secretor phenotype pathways. Enzymes (Secretor or Lewis) add specific modifications to a precursor molecule. Individuals without a functional FUT2 gene cannot express HBGAs from the left branch of the pathway (left of the dotted line) on mucosal surfaces. For those without a functional FUT2 gene (non-secretors), the precursor molecule can still be modified by the Lewis enzyme to make Lewis a antigen (branch on the right side of the dotted line).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475665&req=5

ppat-1002921-g001: NoV Genetic Diversity, Structure, and Binding Ligand.1A:NoV genome schematic. The NoV genome encodes three open reading frames. ORF 1 encodes the nonstructural proteins (blue); ORF 2 encodes VP1, the major capsid protein (purple); and ORF 3 encodes VP2, the minor capsid protein (green). VP1 is further divided into the shell, which forms the base of the virion (teal); the P1 subdomain, which forms a stalk-like projection from the surface (orange); and the P2 subdomain, which is the most variable and surface-exposed area of the virion, contains ligand binding sites, and interacts with potentially neutralizing antibodies (red). 1B: NoV phylogenetic tree. NoVs are divided into five genogroups. Genogroups 1 (pink) and 2 (orange) cause the majority of human disease. Genogroups are further divided into genotypes. Genotype GII.4 NoVs (red bracket) account for ∼80% of outbreaks. Genotype GI.1 NoVs are the prototypic Norwalk viruses. 1C: NoV capsid protein (VP1) cryo EM image. Colors correspond approximately to the shell (teal), the P1 subdomain (yellow/orange) and the P2 subdomain (red). 1D. Secretor/non-secretor phenotype pathways. Enzymes (Secretor or Lewis) add specific modifications to a precursor molecule. Individuals without a functional FUT2 gene cannot express HBGAs from the left branch of the pathway (left of the dotted line) on mucosal surfaces. For those without a functional FUT2 gene (non-secretors), the precursor molecule can still be modified by the Lewis enzyme to make Lewis a antigen (branch on the right side of the dotted line).
Mentions: NoVs are divided into five genogroups (GI-GV), which differ by >60% based on capsid sequence [3], and GI and GII NoVs cause the majority of human disease (Figure 1A–C). Genogroups are further divided into genotypes, which differ by about 40%, with GI.1 as the prototypic “Norwalk” genotype and the GII.4 NoVs as the genotype responsible for the majority (80%) of outbreaks [4]. GII.4 NoVs in particular appear to accommodate a high level of sequence diversity and undergo positive selection in key surface-exposed residues, likely allowing for escape from herd immunity [1], [5]. Differences in evolution rates among different GI and GII NoVs have been attributed to receptor switching and effective population size, VP1 sequence space and structural plasticity, duration of herd immunity, and replication fidelity [1], [6]–[9].

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Noroviruses (NoVs), members of the Calicivirus family, are small, positive-polarity RNA viruses and the most important cause of human foodborne viral gastroenteritis worldwide... Expression of most HBGAs on mucosal tissues is dependent on the presence of a functional FUT2 gene, which codes for a fucosyltransferase that adds side chains to a precursor molecule... About 20% of people do not encode a functional FUT2 gene and are considered “non-secretors” (Figure 1D)... Short-term immunity has previously been established for GI.1 viruses, and a recent vaccine study found that intranasal vaccination with GI.1 VLPs protected against disease three weeks post vaccination... The existence of long-term immunity is more controversial; however, multiple studies found protective responses against GI.1 were present six months after challenge in some but not all individuals, ,... GI and GII antibodies are high in acute sera, while cross-blockade patterns are genogroup-specific, ... Sera against GI outbreaks are cross-blocking within the genogroup and are sometimes higher for a heterologous strain after infection, ; however, the blocking response does not extend to GII NoVs... Importantly, New Orleans 2009 and its recent derivatives demonstrate continued evolution in the major blockade epitopes, suggesting escape from GII.4–2006 herd immunity... While multiple blockade epitopes change over time, conserved, unmapped GII.4 blockade epitopes also exist... No GI or cross-GI and GII antibody blockade epitopes have been mapped, signaling an important priority for future studies... To further characterize the complexity of the molecular mechanisms driving antigenic variation, additional crystal structures in complex with strain, genotype, and genogroup-specific antibodies are needed to define complete epitopes, tease apart overlapping epitopes, and map the exact residues comprising important cross-reactive and cross-blockade epitopes... Human NoV infection or vaccination elicits a primarily CD4+ Th1 response, leading to increased secretion of IFN-gamma and IL-2, ... One study using human-derived PBMCs found that T cell responses were more cross-reactive between GII strains with higher antigenic relatedness, while another study found that T cell responses toward alternate GI strains were more robust than the immunizing GI strain in some individuals... Areas of the capsid undergoing positive selection over time in rapidly evolving NoV genotypes will need to be continuously monitored in order to keep abreast of novel surface variation that may lead to escape from herd immunity and emergence of new pandemic strains... The potential effects a vaccine would have on the evolutionary dynamics of emerging NoV strains will need to be clarified.

Show MeSH
Related in: MedlinePlus