Research

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14 pages, 2748 KiB

Open AccessArticle

Human Norovirus Histo-Blood Group Antigen (HBGA) Binding Sites Mediate the Virus Specific Interactions with Lettuce Carbohydrates

by Malak A. Esseili, Xiang Gao, Patricia Boley, Yixuan Hou, Linda J. Saif, Paul Brewer-Jensen, Lisa C. Lindesmith, Ralph S. Baric, Robert L. Atmar and Qiuhong Wang

Viruses 2019, 11(9), 833; https://doi.org/10.3390/v11090833 - 08 Sep 2019

Cited by 11 | Viewed by 4776

Abstract

Lettuce is often implicated in human norovirus (HuNoV) foodborne outbreaks. We identified H-like histo-blood group antigens (HBGAs) on lettuce leaves as specific binding moieties for virus-like particles (VLPs) of HuNoV GII.4/HS194/2009 strain. The objective of this study was to determine whether HuNoV-lettuce binding [...] Read more.

Lettuce is often implicated in human norovirus (HuNoV) foodborne outbreaks. We identified H-like histo-blood group antigens (HBGAs) on lettuce leaves as specific binding moieties for virus-like particles (VLPs) of HuNoV GII.4/HS194/2009 strain. The objective of this study was to determine whether HuNoV-lettuce binding is mediated through the virus HBGA binding sites (HBS). Toward this objective, VLPs of historical HuNoV GII.4 strains (1987, 1997, 2002, 2004 and 2006) with known natural mutations in their HBS, two newly generated VLP mutants of GII.4/HS194/2009 (D374A and G443A) and a VLP mutant (W375A) of GI.1/Norwalk/1968 along with its wild type VLPs, which displays distinct HBS, were investigated for their binding to lettuce. ELISA revealed that historical GII.4 strains binding to lettuce was dependent on their HBGAs profiles. The VLP mutants D374A and G443A lost binding to HBGAs and displayed no to minimal binding to lettuce, respectively. The VLPs of GI.1/Norwalk/1968 strain bound to lettuce through an H-like HBGA and the binding was inhibited by fucosidase digestion. Mutant W375A which was previously shown not to bind to HBGAs, displayed significantly reduced binding to lettuce. We conclude that the binding of HuNoV GII.4 and GI.1 strains to lettuce is mediated through the virus HBS. Full article

(This article belongs to the Special Issue Noroviruses)

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17 pages, 4148 KiB

Open AccessArticle

Emerging Novel GII.P16 Noroviruses Associated with Multiple Capsid Genotypes

by Leslie Barclay, Jennifer L. Cannon, Mary E. Wikswo, Annie R. Phillips, Hannah Browne, Anna M. Montmayeur, Roman L. Tatusov, Rachel M. Burke, Aron J. Hall and Jan Vinjé

Viruses 2019, 11(6), 535; https://doi.org/10.3390/v11060535 - 08 Jun 2019

Cited by 44 | Viewed by 3933

Abstract

Noroviruses evolve by antigenic drift and recombination, which occurs most frequently at the junction between the non-structural and structural protein coding genomic regions. In 2015, a novel GII.P16-GII.4 Sydney recombinant strain emerged, replacing the predominance of GII.Pe-GII.4 Sydney among US outbreaks. Distinct from [...] Read more.

Noroviruses evolve by antigenic drift and recombination, which occurs most frequently at the junction between the non-structural and structural protein coding genomic regions. In 2015, a novel GII.P16-GII.4 Sydney recombinant strain emerged, replacing the predominance of GII.Pe-GII.4 Sydney among US outbreaks. Distinct from GII.P16 polymerases detected since 2010, this novel GII.P16 was subsequently detected among GII.1, GII.2, GII.3, GII.10 and GII.12 viruses, prompting an investigation on the unique characteristics of these viruses. Norovirus positive samples (n = 1807) were dual-typed, of which a subset (n = 124) was sequenced to yield near-complete genomes. CaliciNet and National Outbreak Reporting System (NORS) records were matched to link outbreak characteristics and case outcomes to molecular data and GenBank was mined for contextualization. Recombination with the novel GII.P16 polymerase extended GII.4 Sydney predominance and increased the number of GII.2 outbreaks in the US. Introduction of the novel GII.P16 noroviruses occurred without unique amino acid changes in VP1, more severe case outcomes, or differences in affected population. However, unique changes were found among NS1/2, NS4 and VP2 proteins, which have immune antagonistic functions, and the RdRp. Multiple polymerase-capsid combinations were detected among GII viruses including 11 involving GII.P16. Molecular surveillance of protein sequences from norovirus genomes can inform the functional importance of amino acid changes in emerging recombinant viruses and aid in vaccine and antiviral formulation. Full article

(This article belongs to the Special Issue Noroviruses)

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19 pages, 1601 KiB

Open AccessArticle

Efficient Production of Human Norovirus-Specific IgY in Egg Yolks by Vaccination of Hens with a Recombinant Vesicular Stomatitis Virus Expressing VP1 Protein

by Yang Zhu, Yuanmei Ma, Mijia Lu, Yu Zhang, Anzhong Li, Xueya Liang and Jianrong Li

Viruses 2019, 11(5), 444; https://doi.org/10.3390/v11050444 - 16 May 2019

Cited by 8 | Viewed by 3388

Abstract

Human norovirus (HuNoV) is responsible for more than 95% of outbreaks of acute nonbacterial gastroenteritis worldwide. Despite major efforts, there are no vaccines or effective therapeutic interventions against this virus. Chicken immunoglobulin Y (IgY)-based passive immunization has been shown to be an effective [...] Read more.

Human norovirus (HuNoV) is responsible for more than 95% of outbreaks of acute nonbacterial gastroenteritis worldwide. Despite major efforts, there are no vaccines or effective therapeutic interventions against this virus. Chicken immunoglobulin Y (IgY)-based passive immunization has been shown to be an effective strategy to prevent and treat many enteric viral diseases. Here, we developed a highly efficient bioreactor to generate high titers of HuNoV-specific IgY in chicken yolks using a recombinant vesicular stomatitis virus expressing HuNoV capsid protein (rVSV-VP1) as an antigen. We first demonstrated that HuNoV VP1 protein was highly expressed in chicken cells infected by rVSV-VP1. Subsequently, we found that White Leghorn hens immunized intramuscularly with rVSV-VP1 triggered a high level of HuNoV-specific yolk IgY antibodies. The purified yolk IgY was efficiently recognized by HuNoV virus-like particles (VLPs). Importantly, HuNoV-specific IgY efficiently blocked the binding of HuNoV VLPs to all three types (A, B, and O) of histo-blood group antigens (HBGAs), the attachment factors for HuNoV. In addition, the receptor blocking activity of IgY remained stable at temperature below 70 °C and at pH ranging from 4 to 9. Thus, immunization of hens with VSV-VP1 could be a cost-effective and practical strategy for large-scale production of anti-HuNoV IgY antibodies for potential use as prophylactic and therapeutic treatment against HuNoV infection. Full article

(This article belongs to the Special Issue Noroviruses)

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21 pages, 1182 KiB

Open AccessArticle

In Depth Breadth Analyses of Human Blockade Responses to Norovirus and Response to Vaccination

by Joel Haynes, Virginia Perry, Evelyn Benson, Alisa Meeks, Gayle Watts, Heather Watkins and Ralph Braun

Viruses 2019, 11(5), 392; https://doi.org/10.3390/v11050392 - 26 Apr 2019

Cited by 8 | Viewed by 3293

Abstract

To evaluate and understand the efficacy of vaccine candidates, supportive immunological measures are needed. Critical attributes for a norovirus vaccine are the strength and breadth of antibody responses against the many different genotypes. In the absence of suitable neutralization assays to test samples [...] Read more.

To evaluate and understand the efficacy of vaccine candidates, supportive immunological measures are needed. Critical attributes for a norovirus vaccine are the strength and breadth of antibody responses against the many different genotypes. In the absence of suitable neutralization assays to test samples from vaccine clinical trials, blockade assays offer a method that can measure functional antibodies specific for many of the different norovirus strains. This paper describes development and optimization of blockade assays for an extended panel of 20 different norovirus strains that can provide robust and reliable data needed for vaccine assessment. The blockade assays were used to test a panel of human clinical samples taken before and after vaccination with the Takeda TAK-214 norovirus vaccine. Great variability was evident in the repertoire of blocking antibody responses prevaccination and postvaccination among individuals. Following vaccination with TAK-214, blocking antibody levels were enhanced across a wide spectrum of different genotypes. The results indicate that adults may have multiple exposures to norovirus and that the magnitude and breadth of the complex preexisting antibody response can be boosted and expanded by vaccination. Full article

(This article belongs to the Special Issue Noroviruses)

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12 pages, 1338 KiB

Open AccessArticle

Epidemiology of Norovirus Outbreaks Reported to the Public Health Emergency Event Surveillance System, China, 2014–2017

by Yiyao Lian, Shuyu Wu, Li Luo, Bin Lv, Qiaohong Liao, Zhongjie Li, Jeanette J. Rainey, Aron J. Hall and Lu Ran

Viruses 2019, 11(4), 342; https://doi.org/10.3390/v11040342 - 11 Apr 2019

Cited by 39 | Viewed by 4959

Abstract

We conducted a retrospective analysis of norovirus outbreaks reported to the National Public Health Emergency Event Surveillance System (PHEESS) in China from January 1, 2014 to December 31, 2017. We reviewed all acute gastroenteritis outbreaks (n = 692) submitted to PHEESS to [...] Read more.

We conducted a retrospective analysis of norovirus outbreaks reported to the National Public Health Emergency Event Surveillance System (PHEESS) in China from January 1, 2014 to December 31, 2017. We reviewed all acute gastroenteritis outbreaks (n = 692) submitted to PHEESS to identify the frequency, seasonality, geographic distribution, setting, and transmission mode of outbreaks due to norovirus. A total of 616 norovirus outbreaks resulting in 30,848 cases were reported. Among these outbreaks, 571 (93%) occurred in school settings including 239 (39%) in primary schools, 136 (22%) in childcare facilities, and 121 (20%) in secondary schools. The majority of outbreaks (63%) were due to person-to-person transmission, followed by multiple modes of transmission (11%), foodborne (5%) and waterborne (3%) transmission. These findings highlight the importance of improving hand hygiene and environmental disinfection in high-risk settings. Developing a standard and quantitative outbreak reporting structure could improve the usefulness of PHEESS for monitoring norovirus outbreaks. Full article

(This article belongs to the Special Issue Noroviruses)

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15 pages, 2786 KiB

Open AccessArticle

Cell Cycle Arrest is a Conserved Function of Norovirus VPg Proteins

by Alice McSweeney, Colin Davies and Vernon K. Ward

Viruses 2019, 11(3), 217; https://doi.org/10.3390/v11030217 - 04 Mar 2019

Cited by 7 | Viewed by 3869

Abstract

Murine norovirus (MNV) viral protein genome-linked (VPg) manipulates the cell cycle to induce a G0/G1 arrest and gain a beneficial replication environment. All viruses of the norovirus genus encode a VPg protein; however, it is unknown if the G0/G1 arrest induced by MNV [...] Read more.

Murine norovirus (MNV) viral protein genome-linked (VPg) manipulates the cell cycle to induce a G0/G1 arrest and gain a beneficial replication environment. All viruses of the norovirus genus encode a VPg protein; however, it is unknown if the G0/G1 arrest induced by MNV VPg is conserved in other members of the genus. RNA transcripts encoding a representative viral VPg from five norovirus genogroups were transfected into RAW-Blue murine macrophages, and the percentage of cells in each phase of the cell cycle was determined. A G0/G1 cell cycle arrest was observed for all norovirus VPg proteins tested, and in the wider Caliciviridae family the arrest was also conserved in rabbit hemorrhagic disease virus (RHDV) VPg and human sapovirus (HuSV) VPg. Truncation of MNV VPg shows that the first 62 amino acids are sufficient for a cell cycle arrest, and alignment of VPg sequences revealed a conserved motif in the N-terminal region of VPg. Analysis of VPg constructs with single N-terminal region point mutations, or exchange of N-terminal regions between VPg proteins, confirmed the importance of the N-terminal region for cell cycle arrest. These results provide evidence that G0/G1 cell cycle arrest is a conserved function of norovirus VPg proteins that involves the N-terminal region of these proteins. Full article

(This article belongs to the Special Issue Noroviruses)

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16 pages, 6019 KiB

Open AccessArticle

Genomics Analyses of GIV and GVI Noroviruses Reveal the Distinct Clustering of Human and Animal Viruses

by Lauren A. Ford-Siltz, Lisa Mullis, Yasser M. Sanad, Kentaro Tohma, Cara J. Lepore, Marli Azevedo and Gabriel I. Parra

Viruses 2019, 11(3), 204; https://doi.org/10.3390/v11030204 - 01 Mar 2019

Cited by 20 | Viewed by 4654

Abstract

Noroviruses are highly diverse viruses that are the major viral cause of acute gastroenteritis in humans. Although these viruses can infect multiple mammalian species, their potential for zoonosis is not well understood, especially within Genogroup IV (GIV), which contains viruses that infect humans, [...] Read more.

Noroviruses are highly diverse viruses that are the major viral cause of acute gastroenteritis in humans. Although these viruses can infect multiple mammalian species, their potential for zoonosis is not well understood, especially within Genogroup IV (GIV), which contains viruses that infect humans, canines, and felines. The study of GIV viruses has been, in part, hindered by the limited number of complete genomes. Here, we developed a full-genome amplicon-based platform that facilitated the sequencing of canine noroviruses circulating in the United States. Eight novel nearly full-length canine norovirus genomes and two nearly complete VP1 sequences, including four GIV.2, three GVI.1, and three GVI.2 viruses, were successfully obtained. Only animal strains exhibited GVI/GIV chimeric viruses, demonstrating restrictions in norovirus recombination. Using genomic, phylogenetic, and structural analyses, we show that differences within the major capsid protein and the non-structural proteins of GIV and GVI noroviruses could potentially limit cross-species transmission between humans, canines, and felines. Full article

(This article belongs to the Special Issue Noroviruses)

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7 pages, 203 KiB

Open AccessArticle

Estimating Disability-Adjusted Life Years (DALYs) in Community Cases of Norovirus in England

by John P. Harris, Miren Iturriza-Gomara and Sarah J. O’Brien

Viruses 2019, 11(2), 184; https://doi.org/10.3390/v11020184 - 21 Feb 2019

Cited by 5 | Viewed by 3726

Abstract

Disability adjusted life years (DALYs) have been used since the 1990s. It is a composite measure of years of life lost with years lived with disability. Essentially, one DALY is the equivalent of a year of healthy life lost if a person had [...] Read more.

Disability adjusted life years (DALYs) have been used since the 1990s. It is a composite measure of years of life lost with years lived with disability. Essentially, one DALY is the equivalent of a year of healthy life lost if a person had not experienced disease. Norovirus is the most common cause of gastrointestinal diseases worldwide. Norovirus activity varies from one season to the next for reasons not fully explained. Infection with norovirus is generally not severe, and is normally characterized as mild and self-limiting with no long-term sequelae. In this study, we model a range of estimates of DALYs for community cases of norovirus in England and Wales. We estimated a range of DALYs for norovirus to account for mixing of the severity of disease and the range of length of illness experienced by infected people. Our estimates were between 1159 and 4283 DALYs per year, or 0.3–1.2 years of healthy life lost per thousand cases of norovirus. These estimates provide evidence that norovirus leads to a considerable level of ill health in England and Wales. This information will be helpful should candidate norovirus vaccines become available in the future. Full article

(This article belongs to the Special Issue Noroviruses)

16 pages, 1108 KiB

Open AccessArticle

The Oxysterol 25-Hydroxycholesterol Inhibits Replication of Murine Norovirus

by Ghada T. Shawli, Oluwapelumi O. Adeyemi, Nicola J. Stonehouse and Morgan R. Herod

Viruses 2019, 11(2), 97; https://doi.org/10.3390/v11020097 - 24 Jan 2019

Cited by 18 | Viewed by 3974

Abstract

Cholesterol, an essential component of mammalian cells, is also an important factor in the replicative-cycles of several human and animal viruses. The oxysterol, 25-hydroxycholesterol, is produced from cholesterol by the enzyme, cholesterol 25-hydroxylase. 25-hydroxycholesterol (25-HC) has been shown to have anti-viral activities against [...] Read more.

Cholesterol, an essential component of mammalian cells, is also an important factor in the replicative-cycles of several human and animal viruses. The oxysterol, 25-hydroxycholesterol, is produced from cholesterol by the enzyme, cholesterol 25-hydroxylase. 25-hydroxycholesterol (25-HC) has been shown to have anti-viral activities against a wide range of viruses, including a range of positive-sense RNA viruses. In this study, we have investigated the role of 25-HC in norovirus replication using murine norovirus (MNV) as a model system. As a control, we employed herpes simplex virus-1 (HSV-1), a pathogen previously shown to be inhibited by 25-HC. Consistent with previous studies, 25-HC inhibited HSV-1 replication in the MNV-susceptible cell line, RAW264.7. Treating RAW264.7 cells with sub-cytotoxic concentrations of 25-HC reduced the MNV titers. However, other sterols such as cholesterol or the oxysterol, 22-S-hydroxycholesterol (22-S-HC), did not inhibit MNV replication. Moreover, treating MNV-infected RAW264.7 cells with 25-HC-stimulated caspase 3/7 activity, which leads to enhanced apoptosis and increased cell death. Our study adds noroviruses to the list of viruses inhibited by 25-HC and begins to offer insights into the mechanism behind this inhibition. Full article

(This article belongs to the Special Issue Noroviruses)

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15 pages, 4817 KiB

Open AccessArticle

Immunological Cross-Reactivity of an Ancestral and the Most Recent Pandemic Norovirus GII.4 Variant

by Kirsi Tamminen, Maria Malm, Timo Vesikari and Vesna Blazevic

Viruses 2019, 11(2), 91; https://doi.org/10.3390/v11020091 - 22 Jan 2019

Cited by 11 | Viewed by 3202

Abstract

Norovirus (NoV) genotype GII.4 is responsible for the majority of NoV infections causing pandemics every few years. A NoV virus-like particle (VLP)-based vaccine should optimally cover the high antigenic variation within the GII.4 genotype. We compared the immune responses generated by VLPs of [...] Read more.

Norovirus (NoV) genotype GII.4 is responsible for the majority of NoV infections causing pandemics every few years. A NoV virus-like particle (VLP)-based vaccine should optimally cover the high antigenic variation within the GII.4 genotype. We compared the immune responses generated by VLPs of the ancestral GII.4 1999 strain (GII.4 1995/96 US variant) and the most recent GII.4 Sydney 2012 pandemic strains in mice. No significant differences were observed in the type-specific responses but GII.4 1999 VLPs were more potent in inducing high-avidity antibodies with better cross-reactivity. GII.4 1999 immune sera blocked binding of GII.4 2006 and GII.4 2012 VLPs to the putative receptors in a surrogate neutralization assay, whereas GII.4 2012 immune sera only had low blocking activity against GII.4 2006 VLPs. Amino acid substitution in the NERK motif (amino acids 310, 316, 484, and 493, respectively), altering the access to conserved blocking epitope F, moderately improved the cross-blocking responses against mutated GII.4 2012 VLPs (D310N). NoV GII.4 1999 VLPs, uptaken and processed by antigen-presenting cells, induced stronger interferon gamma (IFN-γ) production from mice splenocytes than GII.4 2012 VLPs. These results support the use of GII.4 1999 VLPs as a major component of a NoV vaccine. Full article

(This article belongs to the Special Issue Noroviruses)

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17 pages, 4998 KiB

Open AccessArticle

The Microtubule-Associated Innate Immune Sensor GEF-H1 Does Not Influence Mouse Norovirus Replication in Murine Macrophages

by Svenja Fritzlar, Peter A. White and Jason M. Mackenzie

Viruses 2019, 11(1), 47; https://doi.org/10.3390/v11010047 - 10 Jan 2019

Cited by 4 | Viewed by 4848

Abstract

Norovirus is an acute infection of the gastrointestinal tract causing rapid induction of vomiting and diarrhoea. The infection is sensed and controlled by the innate immune system, particularly by the RNA helicase MDA-5 and type I and III interferons (IFNs). We have observed [...] Read more.

Norovirus is an acute infection of the gastrointestinal tract causing rapid induction of vomiting and diarrhoea. The infection is sensed and controlled by the innate immune system, particularly by the RNA helicase MDA-5 and type I and III interferons (IFNs). We have observed that intracellular replication of murine norovirus (MNV) occurs in membranous clusters proximal to the microtubule organising centre, a localisation dependent on intact microtubules. Recently, it was shown that the host protein guanine nucleotide exchange factor-H1 (GEF-H1) is a microtubule-associated innate immune sensor that activates interferon Regulatory Factor 3 to induce the production of type I IFNs. Thus, we interrogated the potential role of GEF-H1 in controlling MNV infections. We observed that GEF-H1 was recruited to the MNV replication complex; however RNAi-mediated suppression of GEF-H1 did not outwardly affect replication. We furthered our studies to investigate the impact of GEF-H1 on MNV innate detection and observed that GEF-H1 did not contribute to type I IFN induction during MNV infection or influenza virus infection but did result in a small reduction of interferon–β (IFNβ) during West Nile virus infection. Intriguingly, we discovered an interaction of GEF-H1 with the viral MNV non-structural protein 3 (NS3), an interaction that altered the location of GEF-H1 within the cell and prevented the formation of GEF-H1-induced microtubule fibres. Thus, our results indicate that GEF-H1 does not contribute significantly to the innate immune sensing of MNV, although its function may be modulated via interaction with the viral NS3 protein. Full article

(This article belongs to the Special Issue Noroviruses)

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Review

Jump to: Research

12 pages, 1512 KiB

Open AccessReview

Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges

by Mary K. Estes, Khalil Ettayebi, Victoria R. Tenge, Kosuke Murakami, Umesh Karandikar, Shih-Ching Lin, B. Vijayalakshmi Ayyar, Nicolas W. Cortes-Penfield, Kei Haga, Frederick H. Neill, Antone R. Opekun, James R. Broughman, Xi-Lei Zeng, Sarah E. Blutt, Sue E. Crawford, Sasirekha Ramani, David Y. Graham and Robert L. Atmar

Viruses 2019, 11(7), 638; https://doi.org/10.3390/v11070638 - 11 Jul 2019

Cited by 74 | Viewed by 7671

Abstract

Noroviruses, in the genus Norovirus, are a significant cause of viral gastroenteritis in humans and animals. For almost 50 years, the lack of a cultivation system for human noroviruses (HuNoVs) was a major barrier to understanding virus biology and the development of [...] Read more.

Noroviruses, in the genus Norovirus, are a significant cause of viral gastroenteritis in humans and animals. For almost 50 years, the lack of a cultivation system for human noroviruses (HuNoVs) was a major barrier to understanding virus biology and the development of effective antiviral strategies. This review presents a historical perspective of the development of a cultivation system for HuNoVs in human intestinal epithelial cell cultures. Successful cultivation was based on the discovery of genetically-encoded host factors required for infection, knowledge of the site of infection in humans, and advances in the cultivation of human intestinal epithelial cells achieved by developmental and stem cell biologists. The human stem cell-derived enteroid cultivation system recapitulates the multicellular, physiologically active human intestinal epithelium, and allows studies of virus-specific replication requirements, evaluation of human host-pathogen interactions, and supports the pre-clinical assessment of methods to prevent and treat HuNoV infections. Full article

(This article belongs to the Special Issue Noroviruses)

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13 pages, 1733 KiB

Open AccessReview

In Vitro Replication of Human Norovirus

by Sutonuka Bhar and Melissa K. Jones

Viruses 2019, 11(6), 547; https://doi.org/10.3390/v11060547 - 12 Jun 2019

Cited by 24 | Viewed by 7417

Abstract

Human norovirus (HuNoV) infection is a major cause of gastroenteritis all over the world. Despite this, these non-enveloped RNA viruses are poorly characterized due to the lack of robust and widely available HuNoV culture systems. The two published systems (B cell line and [...] Read more.

Human norovirus (HuNoV) infection is a major cause of gastroenteritis all over the world. Despite this, these non-enveloped RNA viruses are poorly characterized due to the lack of robust and widely available HuNoV culture systems. The two published systems (B cell line and stem cell-derived enteroids) support replication of HuNoVs but the levels of replication are not sufficient for the generation of highly purified virus stocks or the development of culture-based quantification assays. Therefore, improvement of HuNoV in vitro replication is still needed. Murine norovirus and other caliciviruses have provided insights into norovirus replication that paved the way for the development of the current HuNoV culture systems and may also aid in the improvement of these systems. This review will highlight ways in which previous research guided and impacted the development of HuNoV culture systems and discuss ways in which more recent discoveries might be utilized to improve the quality of the HuNoV in vitro replication. Full article

(This article belongs to the Special Issue Noroviruses)

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13 pages, 1260 KiB

Open AccessReview

Norovirus Attachment and Entry

by Vincent R. Graziano, Jin Wei and Craig B. Wilen

Viruses 2019, 11(6), 495; https://doi.org/10.3390/v11060495 - 30 May 2019

Cited by 38 | Viewed by 12544

Abstract

Human norovirus is a major human pathogen causing the majority of cases of viral gastroenteritis globally. Viral entry is the first step of the viral life cycle and is a significant determinant of cell tropism, host range, immune interactions, and pathogenesis. Bile salts [...] Read more.

Human norovirus is a major human pathogen causing the majority of cases of viral gastroenteritis globally. Viral entry is the first step of the viral life cycle and is a significant determinant of cell tropism, host range, immune interactions, and pathogenesis. Bile salts and histo-blood group antigens are key mediators of norovirus entry; however, the molecular mechanisms by which these molecules promote infection and the identity of a potential human norovirus receptor remain unknown. Recently, there have been several important advances in norovirus entry biology including the identification of CD300lf as the receptor for murine norovirus and of the role of the minor capsid protein VP2 in viral genome release. Here, we will review the current understanding about norovirus attachment and entry and highlight important future directions. Full article

(This article belongs to the Special Issue Noroviruses)

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26 pages, 3237 KiB

Open AccessReview

Animals as Reservoir for Human Norovirus

by Nele Villabruna, Marion P. G. Koopmans and Miranda de Graaf

Viruses 2019, 11(5), 478; https://doi.org/10.3390/v11050478 - 25 May 2019

Cited by 50 | Viewed by 9534

Abstract

Norovirus is the most common cause of non-bacterial gastroenteritis and is a burden worldwide. The increasing norovirus diversity is currently categorized into at least 10 genogroups which are further classified into more than 40 genotypes. In addition to humans, norovirus can infect a [...] Read more.

Norovirus is the most common cause of non-bacterial gastroenteritis and is a burden worldwide. The increasing norovirus diversity is currently categorized into at least 10 genogroups which are further classified into more than 40 genotypes. In addition to humans, norovirus can infect a broad range of hosts including livestock, pets, and wild animals, e.g., marine mammals and bats. Little is known about norovirus infections in most non-human hosts, but the close genetic relatedness between some animal and human noroviruses coupled with lack of understanding where newly appearing human norovirus genotypes and variants are emerging from has led to the hypothesis that norovirus may not be host restricted and might be able to jump the species barrier. We have systematically reviewed the literature to describe the diversity, prevalence, and geographic distribution of noroviruses found in animals, and the pathology associated with infection. We further discuss the evidence that exists for or against interspecies transmission including surveillance data and data from in vitro and in vivo experiments. Full article

(This article belongs to the Special Issue Noroviruses)

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34 pages, 27387 KiB

Open AccessReview

The Antigenic Topology of Norovirus as Defined by B and T Cell Epitope Mapping: Implications for Universal Vaccines and Therapeutics

by Jessica M. van Loben Sels and Kim Y. Green

Viruses 2019, 11(5), 432; https://doi.org/10.3390/v11050432 - 10 May 2019

Cited by 25 | Viewed by 7026

Abstract

Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis. Vaccine design has been confounded by the antigenic diversity of these viruses and a limited understanding of protective immunity. We reviewed 77 articles published since 1988 describing the isolation, function, and mapping [...] Read more.

Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis. Vaccine design has been confounded by the antigenic diversity of these viruses and a limited understanding of protective immunity. We reviewed 77 articles published since 1988 describing the isolation, function, and mapping of 307 unique monoclonal antibodies directed against B cell epitopes of human and murine noroviruses representing diverse Genogroups (G). Of these antibodies, 91, 153, 21, and 42 were reported as GI-specific, GII-specific, MNV GV-specific, and G cross-reactive, respectively. Our goal was to reconstruct the antigenic topology of noroviruses in relationship to mapped epitopes with potential for therapeutic use or inclusion in universal vaccines. Furthermore, we reviewed seven published studies of norovirus T cell epitopes that identified 18 unique peptide sequences with CD4- or CD8-stimulating activity. Both the protruding (P) and shell (S) domains of the major capsid protein VP1 contained B and T cell epitopes, with the majority of neutralizing and HBGA-blocking B cell epitopes mapping in or proximal to the surface-exposed P2 region of the P domain. The majority of broadly reactive B and T cell epitopes mapped to the S and P1 arm of the P domain. Taken together, this atlas of mapped B and T cell epitopes offers insight into the promises and challenges of designing universal vaccines and immunotherapy for the noroviruses. Full article

(This article belongs to the Special Issue Noroviruses)

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19 pages, 2438 KiB

Open AccessReview

Norovirus Infections and Disease in Lower-Middle- and Low-Income Countries, 1997–2018

by Janet Mans

Viruses 2019, 11(4), 341; https://doi.org/10.3390/v11040341 - 10 Apr 2019

Cited by 66 | Viewed by 8383

Abstract

Noroviruses are a major cause of viral gastroenteritis. The burden of the norovirus in low-resource settings is not well-established due to limited data. This study reviews the norovirus prevalence, epidemiology, and genotype diversity in lower-middle-income countries (LMIC) and in low-income countries (LIC). PubMed [...] Read more.

Noroviruses are a major cause of viral gastroenteritis. The burden of the norovirus in low-resource settings is not well-established due to limited data. This study reviews the norovirus prevalence, epidemiology, and genotype diversity in lower-middle-income countries (LMIC) and in low-income countries (LIC). PubMed was searched up to 14 January 2019 for norovirus studies from all LIC and LMIC (World Bank Classification). Studies that tested gastroenteritis cases and/or asymptomatic controls for norovirus by reverse transcription-polymerase chain reaction (RT-PCR) were included. Sixty-four studies, the majority on children <5 years of age, were identified, and 14% (95% confidence interval; CI 14–15, 5158/36,288) of the gastroenteritis patients and 8% (95% CI 7–9, 423/5310) of healthy controls tested positive for norovirus. In LMIC, norovirus was detected in 15% (95% CI 15–16) of cases and 8% (95% CI 8–10) of healthy controls. In LIC, 11% (95% CI 10–12) of symptomatic cases and 9% (95% CI 8–10) of asymptomatic controls were norovirus positive. Norovirus genogroup II predominated overall. GII.4 was the predominant genotype in all settings, followed by GII.3 and GII.6. The most prevalent GI strain was GI.3. Norovirus causes a significant amount of gastroenteritis in low-resource countries, albeit with high levels of asymptomatic infection in LIC and a high prevalence of coinfections. Full article

(This article belongs to the Special Issue Noroviruses)

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23 pages, 819 KiB

Open AccessReview

Final Consumer Options to Control and Prevent Foodborne Norovirus Infections

by Susana Guix, Rosa M. Pintó and Albert Bosch

Viruses 2019, 11(4), 333; https://doi.org/10.3390/v11040333 - 09 Apr 2019

Cited by 22 | Viewed by 6216

Abstract

Norovirus (NoV) causes about one-fifth of all cases of foodborne diseases and is a foremost cause of domestically acquired foodborne acute gastroenteritis and outbreaks. NoV infections are often associated with the consumption of contaminated fresh and ready-to-eat produce, fresh and frozen berries, raw/undercooked [...] Read more.

Norovirus (NoV) causes about one-fifth of all cases of foodborne diseases and is a foremost cause of domestically acquired foodborne acute gastroenteritis and outbreaks. NoV infections are often associated with the consumption of contaminated fresh and ready-to-eat produce, fresh and frozen berries, raw/undercooked bivalve mollusks and products which become contaminated during handling. Despite many industrial efforts to control and prevent NoV contamination of foods, the prevalence of NoV in high-risk foodstuffs at retail is still significant. Although certain consumer behaviors may even increase the risk of virus transmission, interventions aiming at changing/implementing consumer habits may be considered as opportunities for risk mitigation. This review aims at providing an update on the progress made in characterizing the effect that consumer habits, which are most critical to prevent NoV transmission (food choice and hygiene, disinfection and cooking during food preparation), may have on reducing the risk of NoV infection. A better understanding of the options for NoV control and prevention may be translated into innovative educational, social or even technological tools targeting consumers with the objective of mitigating the risk of NoV transmission. Full article

(This article belongs to the Special Issue Noroviruses)

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15 pages, 1285 KiB

Open AccessReview

Caliciviridae Other Than Noroviruses

by Ulrich Desselberger

Viruses 2019, 11(3), 286; https://doi.org/10.3390/v11030286 - 21 Mar 2019

Cited by 44 | Viewed by 7398

Abstract

Besides noroviruses, the Caliciviridae family comprises four other accepted genera: Sapovirus, Lagovirus, Vesivirus, and Nebovirus. There are six new genera proposed: Recovirus, Valovirus, Bavovirus, Nacovirus, Minovirus, and Salovirus. All Caliciviridae have closely related genome structures, but are genetically and antigenically [...] Read more.

Besides noroviruses, the Caliciviridae family comprises four other accepted genera: Sapovirus, Lagovirus, Vesivirus, and Nebovirus. There are six new genera proposed: Recovirus, Valovirus, Bavovirus, Nacovirus, Minovirus, and Salovirus. All Caliciviridae have closely related genome structures, but are genetically and antigenically highly diverse and infect a wide range of mammalian host species including humans. Recombination in nature is not infrequent for most of the Caliciviridae, contributing to their diversity. Sapovirus infections cause diarrhoea in pigs, humans and other mammalian hosts. Lagovirus infections cause systemic haemorrhagic disease in rabbits and hares, and vesivirus infections lead to lung disease in cats, vesicular disease in swine, and exanthema and diseases of the reproductive system in large sea mammals. Neboviruses are an enteric pathogen of cattle, differing from bovine norovirus. At present, only a few selected caliciviruses can be propagated in cell culture (permanent cell lines or enteroids), and for most of the cultivatable caliciviruses helper virus-free, plasmid only-based reverse genetics systems have been established. The replication cycles of the caliciviruses are similar as far as they have been explored: viruses interact with a multitude of cell surface attachment factors (glycans) and co-receptors (proteins) for adsorption and penetration, use cellular membranes for the formation of replication complexes and have developed mechanisms to circumvent innate immune responses. Vaccines have been developed against lagoviruses and vesiviruses, and are under development against human noroviruses. Full article

(This article belongs to the Special Issue Noroviruses)

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8 pages, 212 KiB

Open AccessReview

Autophagy and Noroviruses

by Kevin Furlong and Seungmin Hwang

Viruses 2019, 11(3), 244; https://doi.org/10.3390/v11030244 - 12 Mar 2019

Cited by 6 | Viewed by 3384

Abstract

Autophagy is an essential cellular process by which a cell degrades materials within its cytoplasm. Intracellular pathogens like viruses must deal with autophagy, either positively or negatively, for their own survival and replication. For some viruses, autophagy can even play proviral roles, helping [...] Read more.

Autophagy is an essential cellular process by which a cell degrades materials within its cytoplasm. Intracellular pathogens like viruses must deal with autophagy, either positively or negatively, for their own survival and replication. For some viruses, autophagy can even play proviral roles, helping their replication or dissemination. For other viruses, including noroviruses, the exact role of autophagy is more complex. This short review seeks to summarize the known interactions between autophagy, autophagy proteins and norovirus, and to address remaining questions relevant to these interactions. Full article

(This article belongs to the Special Issue Noroviruses)

18 pages, 44769 KiB

Open AccessReview

The Dynamic Capsid Structures of the Noroviruses

by Hong Q. Smith and Thomas J. Smith

Viruses 2019, 11(3), 235; https://doi.org/10.3390/v11030235 - 08 Mar 2019

Cited by 27 | Viewed by 8459

Abstract

Noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. New strains evolve every 2–4 years by escaping herd immunity and cause worldwide epidemics. In the US alone, noroviruses are responsible for ~20 million cases and more than 70,000 hospitalizations [...] Read more.

Noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. New strains evolve every 2–4 years by escaping herd immunity and cause worldwide epidemics. In the US alone, noroviruses are responsible for ~20 million cases and more than 70,000 hospitalizations of infected children, annually. Efforts towards a vaccine have been hindered by a lack of detailed structural information about antibody binding and the mechanisms of antibody escape. Caliciviruses have 180 copies of the major capsid protein (VP1; ~58 kDa), that is divided into the N-terminus (N), the shell (S) and C-terminal protruding (P) domains. The S domain forms a shell around the viral RNA genome, while the P domains dimerize to form protrusions on the capsid surface. The P domain is subdivided into P1 and P2 subdomains, with the latter containing the binding sites for cellular receptors and neutralizing antibodies. There is increasing evidence that these viruses are extremely dynamic and this flexibility is critical for viral replication. There are at least two modes of flexibility; the entire P domain relative to the shell and within the P domain itself. Here, the details and possible roles for this remarkable flexibility will be reviewed. Full article

(This article belongs to the Special Issue Noroviruses)

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19 pages, 707 KiB

Open AccessReview

Genetic Susceptibility to Human Norovirus Infection: An Update

by Johan Nordgren and Lennart Svensson

Viruses 2019, 11(3), 226; https://doi.org/10.3390/v11030226 - 06 Mar 2019

Cited by 108 | Viewed by 37408

Abstract

Noroviruses are the most common etiological agent of acute gastroenteritis worldwide. Despite their high infectivity, a subpopulation of individuals is resistant to infection and disease. This susceptibility is norovirus genotype-dependent and is largely mediated by the presence or absence of human histo-blood group [...] Read more.

Noroviruses are the most common etiological agent of acute gastroenteritis worldwide. Despite their high infectivity, a subpopulation of individuals is resistant to infection and disease. This susceptibility is norovirus genotype-dependent and is largely mediated by the presence or absence of human histo-blood group antigens (HBGAs) on gut epithelial surfaces. The synthesis of these HBGAs is mediated by fucosyl- and glycosyltransferases under the genetic control of the FUT2 (secretor), FUT3 (Lewis) and ABO(H) genes. The so-called non-secretors, having an inactivated FUT2 enzyme, do not express blood group antigens and are resistant to several norovirus genotypes, including the predominant GII.4. Significant genotypic and phenotypic diversity of HBGA expression exists between different human populations. Here, we review previous in vivo studies on genetic susceptibility to norovirus infection. These are discussed in relation to population susceptibility, vaccines, norovirus epidemiology and the impact on public health. Full article

(This article belongs to the Special Issue Noroviruses)

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14 pages, 1614 KiB

Open AccessReview

Specific Interactions between Human Norovirus and Environmental Matrices: Effects on the Virus Ecology

by Mohan Amarasiri and Daisuke Sano

Viruses 2019, 11(3), 224; https://doi.org/10.3390/v11030224 - 05 Mar 2019

Cited by 22 | Viewed by 5749

Abstract

Human norovirus is the major cause of non-bacterial epidemic gastroenteritis. Human norovirus binds to environmental solids via specific and non-specific interactions, and several specific receptors for human norovirus have been reported. Among them, histo-blood group antigens (HBGA) are the most studied specific receptor. [...] Read more.

Human norovirus is the major cause of non-bacterial epidemic gastroenteritis. Human norovirus binds to environmental solids via specific and non-specific interactions, and several specific receptors for human norovirus have been reported. Among them, histo-blood group antigens (HBGA) are the most studied specific receptor. Studies have identified the presence of HBGA-like substances in the extracellular polymeric substances (EPS) and lipopolysaccharides (LPS) of human enteric bacteria present in aquatic environments, gastrointestinal cells, gills, and palps of shellfish, and cell walls, leaves, and veins of lettuce. These HBGA-like substances also interact with human norovirus in a genotype-dependent manner. Specific interactions between human norovirus and environmental matrices can affect norovirus removal, infectivity, inactivation, persistence, and circulation. This review summarizes the current knowledge and future directions related to the specific interactions between human norovirus and HBGA-like substances in environmental matrices and their possible effects on the fate and circulation of human norovirus. Full article

(This article belongs to the Special Issue Noroviruses)

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14 pages, 3302 KiB

Open AccessReview

Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

by Kyeong-Ok Chang, Yunjeong Kim, Scott Lovell, Athri D. Rathnayake and William C. Groutas

Viruses 2019, 11(2), 197; https://doi.org/10.3390/v11020197 - 25 Feb 2019

Cited by 44 | Viewed by 9375

Abstract

Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense [...] Read more.

Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors. Full article

(This article belongs to the Special Issue Noroviruses)

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13 pages, 1618 KiB

Open AccessReview

GII.4 Human Norovirus: Surveying the Antigenic Landscape

by Michael L. Mallory, Lisa C. Lindesmith, Rachel L. Graham and Ralph S. Baric

Viruses 2019, 11(2), 177; https://doi.org/10.3390/v11020177 - 20 Feb 2019

Cited by 39 | Viewed by 6095

Abstract

Human norovirus is the leading cause of viral acute onset gastroenteritis disease burden, with 685 million infections reported annually. Vulnerable populations, such as children under the age of 5 years, the immunocompromised, and the elderly show a need for inducible immunity, as symptomatic [...] Read more.

Human norovirus is the leading cause of viral acute onset gastroenteritis disease burden, with 685 million infections reported annually. Vulnerable populations, such as children under the age of 5 years, the immunocompromised, and the elderly show a need for inducible immunity, as symptomatic dehydration and malnutrition can be lethal. Extensive antigenic diversity between genotypes and within the GII.4 genotype present major challenges for the development of a broadly protective vaccine. Efforts have been devoted to characterizing antibody-binding interactions with dynamic human norovirus viral-like particles, which recognize distinct antigenic sites on the capsid. Neutralizing antibody functions recognizing these sites have been validated in both surrogate (ligand blockade of binding) and in vitro virus propagation systems. In this review, we focus on GII.4 capsid protein epitopes as defined by monoclonal antibody binding. As additional antibody epitopes are defined, antigenic sites emerge on the human norovirus capsid, revealing the antigenic landscape of GII.4 viruses. These data may provide a road map for the design of candidate vaccine immunogens that induce cross-protective immunity and the development of therapeutic antibodies and drugs. Full article

(This article belongs to the Special Issue Noroviruses)

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18 pages, 8738 KiB

Open AccessReview

Targeting the Viral Polymerase of Diarrhea-Causing Viruses as a Strategy to Develop a Single Broad-Spectrum Antiviral Therapy

by Marcella Bassetto, Jana Van Dycke, Johan Neyts, Andrea Brancale and Joana Rocha-Pereira

Viruses 2019, 11(2), 173; https://doi.org/10.3390/v11020173 - 20 Feb 2019

Cited by 22 | Viewed by 6396

Abstract

Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against [...] Read more.

Viral gastroenteritis is an important cause of morbidity and mortality worldwide, being particularly severe for children under the age of five. The most common viral agents of gastroenteritis are noroviruses, rotaviruses, sapoviruses, astroviruses and adenoviruses, however, no specific antiviral treatment exists today against any of these pathogens. We here discuss the feasibility of developing a broad-spectrum antiviral treatment against these diarrhea-causing viruses. This review focuses on the viral polymerase as an antiviral target, as this is the most conserved viral protein among the diverse viral families to which these viruses belong to. We describe the functional and structural similarities of the different viral polymerases, the antiviral effect of reported polymerase inhibitors and highlight common features that might be exploited in an attempt of designing such pan-polymerase inhibitor. Full article

(This article belongs to the Special Issue Noroviruses)

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15 pages, 937 KiB

Open AccessReview

Human Norovirus: Experimental Models of Infection

by Kyle V. Todd and Ralph A. Tripp

Viruses 2019, 11(2), 151; https://doi.org/10.3390/v11020151 - 12 Feb 2019

Cited by 33 | Viewed by 5905

Abstract

Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. HuNoV infections lead to substantial societal and economic burdens. There are currently no licensed vaccines or therapeutics for the prevention or treatment of HuNoVs. A lack of well-characterized in vitro and in [...] Read more.

Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. HuNoV infections lead to substantial societal and economic burdens. There are currently no licensed vaccines or therapeutics for the prevention or treatment of HuNoVs. A lack of well-characterized in vitro and in vivo infection models has limited the development of HuNoV countermeasures. Experimental infection of human volunteers and the use of related viruses such as murine NoV have provided helpful insights into HuNoV biology and vaccine and therapeutic development. There remains a need for robust animal models and reverse genetic systems to further HuNoV research. This review summarizes available HuNoV animal models and reverse genetic systems, while providing insight into their usefulness for vaccine and therapeutic development. Full article

(This article belongs to the Special Issue Noroviruses)

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