A Working Model of How Noroviruses Infect the Intestine

Karst, Stephanie M.; Wobus, Christiane E.

doi:10.1371/journal.ppat.1004626

Cited by 79 publications

(73 citation statements)

References 45 publications

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“…MNV transmission via the fecal-oral route requires mechanisms for crossing the epithelial barrier from the intestinal lumen into the lamina propria to initiate infection of immune cells (2,40). Possible mechanisms for crossing the barrier include breaking intestinal membrane tight junctions (41), directly infecting intestinal epithelial cells (42), and using transcellular pores (43), dendritic processes (44), and M cells (18).…”

Section: Discussionmentioning

confidence: 99%

Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells

Kolawole

Gonzalez-Hernandez

Turula

et al. 2016

J Virol

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Section: Discussionmentioning

confidence: 99%

Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells

Kolawole

Gonzalez-Hernandez

Turula

et al. 2016

J Virol

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“…Second, we have identified five residues in the P domain of the MuNoV VP1 protein that regulate infection of B cells and virulence. NoVs are known to infect a variety of immune cell types (16), but the biological relevance of each target cell type is unknown. Moreover, the mediators of pathogenesis during NoV infections are not well established.…”

Section: Figmentioning

confidence: 99%

Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency

Zhu

Watanabe

Kirkpatrick

et al. 2016

J Virol

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Human noroviruses are a leading cause of gastroenteritis across the globe, but the pathogenic mechanisms responsible for disease are not well established. The availability of a murine norovirus model system provides the opportunity to elucidate viral and host determinants of virulence in a natural host. For example, previous studies have revealed that the protruding domain of the murine norovirus capsid protein VP1, specifically residue 296 of VP1, regulates virulent infection. We identified a panel of nonsynonymous mutations in the open reading frame 2 (ORF2) gene encoding VP1 that arose in persistently infected mice and tested whether these mutations conferred phenotypic changes to viral replication and virulence. Consistent with previous studies, we demonstrate that a glutamic acid at position 296 results in attenuation. For the first time, we also demonstrate that a lysine at this position is sufficient to confer virulence on an otherwise attenuated murine norovirus strain. Moreover, our studies reveal a direct correlation between the efficiency of viral replication in B cells and virulence. These data are especially striking because mutations causing reduced B cell replication and attenuation had minimal effects on the ability of the virus to replicate in macrophages. Thus, norovirus infection of B cells may directly contribute to disease outcome. IMPORTANCE Human noroviruses are a major global cause of disease, yet we know very little about their pathogenic mechanisms. The availability of a murine norovirus model system facilitates investigation of noroviruses in a natural host organism and the identification of viral and host determinants of pathogenesis. We have identified a panel of mutations arising in the viral capsid protein VP1 during persistent infection of mice. Our data reveal that the protruding domain of VP1 regulates the ability of the virus to replicate in B cells, and this directly correlates with virulence. Importantly, mutations impairing B cell infection had minimal effects on macrophage infection, revealing a potentially critical role for B cell infection in norovirus pathogenesis.H uman noroviruses (HuNoVs) are the major cause of nonbacterial gastroenteritis worldwide, causing rapid bouts of nausea, severe vomiting, and watery diarrhea in all age groups. They are the leading cause of foodborne disease globally and of severe childhood diarrhea in parts of the world where rotavirus vaccination is being implemented (1-3). Although HuNoV infection is typically self-limited in immunocompetent adults, more severe consequences can occur in risk groups, including the elderly, immunocompromised and transplant patients, and infants (4-6). Considering the huge disease burden attributable to HuNoV infections (7) and the tremendous economic loss associated with these infections (8), development of effective therapeutics and vaccines is highly warranted. However, HuNoV studies are greatly hampered by the lack of robust culturing systems and small-animal models. Although there have been exciti...

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“…Interestingly, sialic acids are distributed largely on the surfaces of certain enteric bacteria as well (53,54). Thus, it is reasonable to speculate that HBGA-expressing bacteria may play key roles as binding partners in the enrichment of NoVs in oysters (55). While this hypothesis remains speculative and requires further evaluation, it potentially helps to explain the diversity of NoV genotypes found in oysters with limited HBGAs (types A and O).…”

Section: Gu726163) Was Isolated From Oyster Samples In Hong Kong In mentioning

confidence: 99%

Molecular Epidemiology of Oyster-Related Human Noroviruses and Their Global Genetic Diversity and Temporal-Geographical Distribution from 1983 to 2014

Cai

et al. 2015

Appl Environ Microbiol

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c Noroviruses (NoVs) are a leading cause of epidemic and sporadic cases of acute gastroenteritis worldwide. Oysters are well recognized as the main vectors of environmentally transmitted NoVs, and disease outbreaks linked to oyster consumption have been commonly observed. Here, to quantify the genetic diversity, temporal distribution, and circulation of oyster-related NoVs on a global scale, 1,077 oyster-related NoV sequences deposited from 1983 to 2014 were downloaded from both NCBI GenBank and the NoroNet outbreak database and were then screened for quality control. A total of 665 sequences with reliable information were obtained and were subsequently subjected to genotyping and phylogenetic analyses. The results indicated that the majority of oyster-related NoV sequences were obtained from coastal countries and regions and that the numbers of sequences in these regions were unevenly distributed. Moreover, >80% of human NoV genotypes were detected in oyster samples or oysterrelated outbreaks. A higher proportion of genogroup I (GI) (34%) was observed for oyster-related sequences than for nonoyster-related outbreaks, where GII strains dominated with an overwhelming majority of >90%, indicating that the prevalences of GI and GII are different in humans and oysters. In addition, a related convergence of the circulation trend was found between oyster-related NoV sequences and human pandemic outbreaks. This suggests that oysters not only act as a vector of NoV through environmental transmission but also serve as an important reservoir of human NoVs. These results highlight the importance of oysters in the persistence and transmission of human NoVs in the environment and have important implications for the surveillance of human NoVs in oyster samples. N orovirus (NoV) is known as the leading cause of nonbacterial acute gastroenteritis in humans and can infect people of all ages across the world (1). As a member of the family Caliciviridae, NoV is a nonenveloped, positive-sense, single-stranded RNA virus with a linear genome that contains three open reading frames (ORFs) (2). The genus Norovirus currently contains at least 6 distinct genogroups (genogroup I [GI], GII, GIII, GIV, GV, and GVI), each of which has been subdivided into multiple genotypes (3, 4). GI, GII, and GIV strains have been detected in humans and are further subdivided into 9, 22, and 2 genotypes, respectively (3, 4). One important genotype, genogroup II genotype 4 (GII.4), has been recognized recently as the predominant cause of major viral gastroenteritis epidemics worldwide (5-7) and contains a number of genetic variants (4,8).Over the past 20 years, new epidemic variants of GII.4 have emerged every 2 to 3 years (9) and usually have become the dominant strains in every season (7, 10, 11). For example, the Yerseke 2006a variant emerged in 2006, disappeared in 2008, and was replaced by the Den Haag 2006b variant (see Fig. S1 in the supplemental material). The New Orleans 2009 variant was the major player in the worldwide NoV outbreaks from 2010 to ...

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A Working Model of How Noroviruses Infect the Intestine

Cited by 79 publications

References 45 publications

Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells

Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells

Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency

Molecular Epidemiology of Oyster-Related Human Noroviruses and Their Global Genetic Diversity and Temporal-Geographical Distribution from 1983 to 2014

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