Structural heterogeneity of a human norovirus vaccine candidate

Devant, J; Hansman, Grant S.

doi:10.1016/j.virol.2020.10.005

Cited by 23 publications

(12 citation statements)

References 48 publications

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“…1 ). As first observed in MNV 22 , 30 , 31 , recent structural studies 21 , 23 – 25 , 28 on HuNoV VLPs have shown that VP1 can exist in two distinct conformations, the “resting” conformation in which the P-domain closely interacts with the S-domain, and the “raised” conformation in which the P-domain is rotated and raised above the S-domain, which is driven either by the removal of stabilizing ions, as in the case of GII.4 VLPs 28 , or with increase in pH, as in case of MNV 21 . The P-domain is further divided into P1 and P2 subdomains, with the distal P2 subdomain involved in recognition of cell attachment factors, which is in the case of GII.4 HuNoV are the histo-blood group antigens (HBGAs) that are also the susceptibility factors 32 , 33 (see Supplementary Fig.…”

Section: Introductionsupporting

confidence: 60%

A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity

Salmen,

Hu,

Bok

et al. 2023

Nat Commun

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Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed a conserved epitope, away from the HBGA binding site, fully accessible only when VP1 transitions to a “raised” conformation in the capsid. Together with dynamic light scattering and electron microscopy of the GII.4 VLPs, our studies suggest a mechanism in which M4 accesses the epitope by altering the conformational dynamics of the capsid and triggering its disassembly to neutralize GII.4 infection.

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Section: Introductionsupporting

confidence: 60%

A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity

Salmen,

Hu,

Bok

et al. 2023

Nat Commun

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“…VLPs were used for many of our entry studies because infectious virus cannot yet be passaged indefinitely and current yields of virus from infected HIEs are not sufficient to produce purified particles for extensive biochemical studies. Since 1992, when HuNoV VLPs were first produced and characterized 38 , they have been extensively documented as useful surrogates for studies of virus structure [39][40][41][42] , antigenicity, immunogenicity, and glycan binding [43][44][45] . Here, we validated that VLPs are useful for studying virus entry by documenting their effectiveness as competitors of homologous virus replication.…”

Section: Discussionmentioning

confidence: 99%

CLIC and membrane wound repair pathways enable pandemic norovirus entry and infection

et al. 2023

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Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell (S) domain interacts with both galectin-3 (gal-3) and apoptosis-linked gene 2-interacting protein X (ALIX), to orchestrate GII.4 cell entry. Recognition of the viral and cellular determinants regulating HuNoV entry provides insight into the infection process of a non-enveloped virus highlighting unique pathways and targets for developing effective therapeutics.

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“…We noted that the PVNPs formed by the S-HA1 proteins were heterologous in sizes. This was not unexpected, because in vitro expression of NoV VP1s often leads to VLP formation at heterologous sizes, including those in T = 1 (~ 31 nm), 3 (~ 46 nm), and 4 (~ 50 nm) icosahedral symmetry, consisting of 60, 180, and 240 NoV VP1s, respectively [49,50]. By focusing on the major populations of the His-tagged H7 PVNPs, we have reconstructed the 3D structures of two PVNPs with distinct diameters (21 nm vs. 16 nm) by cryoEM method, revealing the same T = 1 icosahedral symmetry, being composed of 60 copies of the S-HA1 fusion proteins.…”

Section: Discussionmentioning

confidence: 90%

Bioengineered pseudovirus nanoparticles displaying the HA1 antigens of influenza viruses for enhanced immunogenicity

et al. 2022

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Even with implementation of current influenza vaccines, influenza still claims up to 500,000 lives worldwide annually, indicating a need for a better vaccine strategy. We have developed a technology to generate unique S 60 -HA1 pseudovirus nanoparticles (PVNPs) that display the receptor-binding HA1 domains of influenza viruses. Each self-assembled S 60 -HA1 PVNP consists of a T = 1 icosahedral S 60 nanoparticle that resembles the inner shell of norovirus capsid and 60 surface-displayed HA1 antigens that are excellent vaccine targets. Soluble S 60 -HA1 PVNPs presenting HA1 antigens of H7N9 influenza virus subtypes have been produced efficiently in large amount. Their three-dimensional (3D) structures have been solved by cryogenic electron microscopy. The PVNP-displayed HA1 antigens react with HA-specific antibody, and retain authentic sialic acid binding specificity and hemagglutinate human erythrocytes. The PVNPs are highly immunogenic, eliciting high titers of HA1-specific antibodies in mice and the mouse sera strongly inhibited hemagglutinations of homologous and heterologous influenza virus HA proteins. Therefore, the S 60 -HA1 PVNPs may provide useful reagents to study influenza viruses and offer a potential new vaccine tactic to fight the deadly influenza disease.

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Structural heterogeneity of a human norovirus vaccine candidate

Cited by 23 publications

References 48 publications

A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity

A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity

CLIC and membrane wound repair pathways enable pandemic norovirus entry and infection

Bioengineered pseudovirus nanoparticles displaying the HA1 antigens of influenza viruses for enhanced immunogenicity

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