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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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GII.4 NoV Variation over Time.2A: GII.4 blockade epitopes. Three blockade epitopes have been identified in GII.4 NoVs. Epitope A (residues 294, 296–298, 368, and 372; green), Epitope D (residues 393–395; orange), and Epitope E (residues 407, 412–413; yellow) all map to the P2 subdomain on the surface of the virion. The HBGA interaction sites are shown in black. 2B: GII.4 P2 subdomain variation over time. Colored residues indicate change over time since 1974; changes present in 1987 = yellow, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, 2009 = blue, HBGA interaction sites = black, carbohydrates = white sticks. 2C: GII.4 NoV variation over time in blockade-epitope regions. GII.4 NoV blockade epitopes undergo change over time, likely in response to human herd immunity. Colors indicate in which outbreak strain a particular residue change originated. 2D: Mapping of GII.4 variation over time in blockade-epitope regions. Each VLP shows areas within blockade epitopes that change over time. Yellow indicates differences from 1974 present in 1987, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, and 2009 = blue. These blockade epitopes have continued to evolve in new outbreak strains since 2009.
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ppat-1002921-g002: GII.4 NoV Variation over Time.2A: GII.4 blockade epitopes. Three blockade epitopes have been identified in GII.4 NoVs. Epitope A (residues 294, 296–298, 368, and 372; green), Epitope D (residues 393–395; orange), and Epitope E (residues 407, 412–413; yellow) all map to the P2 subdomain on the surface of the virion. The HBGA interaction sites are shown in black. 2B: GII.4 P2 subdomain variation over time. Colored residues indicate change over time since 1974; changes present in 1987 = yellow, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, 2009 = blue, HBGA interaction sites = black, carbohydrates = white sticks. 2C: GII.4 NoV variation over time in blockade-epitope regions. GII.4 NoV blockade epitopes undergo change over time, likely in response to human herd immunity. Colors indicate in which outbreak strain a particular residue change originated. 2D: Mapping of GII.4 variation over time in blockade-epitope regions. Each VLP shows areas within blockade epitopes that change over time. Yellow indicates differences from 1974 present in 1987, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, and 2009 = blue. These blockade epitopes have continued to evolve in new outbreak strains since 2009.

Mentions: Classic approaches for mapping epitopes cannot be applied to NoV because of the lack of a cell culture system for isolating antibody escape mutants. For G1 NoVs, point and deletion mutations have identified regions of VP1 targeted by antibodies [26], [27]. For GII.4 strains, epitope mapping has been done primarily by using bioinformatics approaches to identify rapidly evolving amino acid residues and exchanging these regions between strains [7]–[9], [28] (Figure 2B). This has allowed for precise mapping of key residues that drive antigenic change in response to human and rodent antibody binding and blockade responses. These mapping studies define key sites of antigenic change; however, the actual antibody binding epitope is usually conformational and likely includes proximal conserved and varying residues that contribute to escape from human herd immunity. A recent crystallography study mapped the binding of a cross-reactive GII monoclonal antibody in complex with a GII.10 P particle to a highly conserved, occluded site within the P1 subdomain, suggesting that the NoV P domain may accommodate high conformational flexibility [29].


Norovirus immunity and the great escape.

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

GII.4 NoV Variation over Time.2A: GII.4 blockade epitopes. Three blockade epitopes have been identified in GII.4 NoVs. Epitope A (residues 294, 296–298, 368, and 372; green), Epitope D (residues 393–395; orange), and Epitope E (residues 407, 412–413; yellow) all map to the P2 subdomain on the surface of the virion. The HBGA interaction sites are shown in black. 2B: GII.4 P2 subdomain variation over time. Colored residues indicate change over time since 1974; changes present in 1987 = yellow, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, 2009 = blue, HBGA interaction sites = black, carbohydrates = white sticks. 2C: GII.4 NoV variation over time in blockade-epitope regions. GII.4 NoV blockade epitopes undergo change over time, likely in response to human herd immunity. Colors indicate in which outbreak strain a particular residue change originated. 2D: Mapping of GII.4 variation over time in blockade-epitope regions. Each VLP shows areas within blockade epitopes that change over time. Yellow indicates differences from 1974 present in 1987, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, and 2009 = blue. These blockade epitopes have continued to evolve in new outbreak strains since 2009.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475665&req=5

ppat-1002921-g002: GII.4 NoV Variation over Time.2A: GII.4 blockade epitopes. Three blockade epitopes have been identified in GII.4 NoVs. Epitope A (residues 294, 296–298, 368, and 372; green), Epitope D (residues 393–395; orange), and Epitope E (residues 407, 412–413; yellow) all map to the P2 subdomain on the surface of the virion. The HBGA interaction sites are shown in black. 2B: GII.4 P2 subdomain variation over time. Colored residues indicate change over time since 1974; changes present in 1987 = yellow, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, 2009 = blue, HBGA interaction sites = black, carbohydrates = white sticks. 2C: GII.4 NoV variation over time in blockade-epitope regions. GII.4 NoV blockade epitopes undergo change over time, likely in response to human herd immunity. Colors indicate in which outbreak strain a particular residue change originated. 2D: Mapping of GII.4 variation over time in blockade-epitope regions. Each VLP shows areas within blockade epitopes that change over time. Yellow indicates differences from 1974 present in 1987, 1997 = red, 2002 = teal, 2004 = green, 2005 = orange, 2006 = purple, and 2009 = blue. These blockade epitopes have continued to evolve in new outbreak strains since 2009.
Mentions: Classic approaches for mapping epitopes cannot be applied to NoV because of the lack of a cell culture system for isolating antibody escape mutants. For G1 NoVs, point and deletion mutations have identified regions of VP1 targeted by antibodies [26], [27]. For GII.4 strains, epitope mapping has been done primarily by using bioinformatics approaches to identify rapidly evolving amino acid residues and exchanging these regions between strains [7]–[9], [28] (Figure 2B). This has allowed for precise mapping of key residues that drive antigenic change in response to human and rodent antibody binding and blockade responses. These mapping studies define key sites of antigenic change; however, the actual antibody binding epitope is usually conformational and likely includes proximal conserved and varying residues that contribute to escape from human herd immunity. A recent crystallography study mapped the binding of a cross-reactive GII monoclonal antibody in complex with a GII.10 P particle to a highly conserved, occluded site within the P1 subdomain, suggesting that the NoV P domain may accommodate high conformational flexibility [29].

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