Human Norovirus Evolution in a Chronically Infected Host

Doerflinger, Sylvie Y.; Weichert, Stefan; Koromyslova, A.D.; Chan, Martin C.W.; Schwerk, Christian; Adam, Rony A.; Jennewein, Stefan; Hansman, Grant S.; Schroten, Horst

doi:10.1128/msphere.00352-16

Cited by 29 publications

(33 citation statements)

References 48 publications

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“…Consistently with the studies mentioned above, in a clinical retrospective study a correlation between high levels of α2′‐linked fucosylated HMOs in breast milk and protection against Calicivirus ‐associated diarrhea has been reported . Further investigations should also consider 3‐fucosyllactose and 3‐fucosylated HMOs, as they also bound at the HBGA binding site in the X‐ray crystallography and MS/MS studies …”

Section: Role Of Glycans In the Viral Attachmentsupporting

confidence: 75%

Human Milk Oligosaccharides as Promising Antivirals

Morozov

Hansman

Hanisch

et al. 2018

Molecular Nutrition Food Res

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104

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Human milk oligosaccharides (HMOs) are diverse unconjugated carbohydrates that are highly abundant in human breast milk. These glycans are investigated in the context of exhibiting multiple functions in infant growth and development. They seem to provide protection against infectious diseases, including a number of poorly manageable viral infections. Although the potential mechanism of the HMO antiviral protection is rather broad, much of the current experimental work has focused on studying of HMO antiadhesive properties. HMOs may mimic structures of viral receptors and block adherence to target cells, thus preventing infection. Still, the potential of HMOs as a source for new antiviral drugs is relatively unexploited. This can be partly attributed to the extreme complexity of the virus-carbohydrate interactions and technical difficulties in HMO isolation, characterization, and manufacturing procedures. Fortunately, we are currently entering a period of major technological advances that have enabled deeper insights into carbohydrate mediated viral entry, rational selection of HMOs as anti-entry inhibitors, and even evaluation of individual synthetic HMO structures. Here, we provide an up-to-date review on glycan binding studies for rotaviruses, noroviruses, influenza viruses, and human immunodeficiency viruses. We also discuss the preventive and therapeutic potential of HMOs as anti-entry inhibitors and address challenges on the route from fundamental studies to clinical trials.

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Section: Role Of Glycans In the Viral Attachmentsupporting

confidence: 75%

Human Milk Oligosaccharides as Promising Antivirals

Morozov

Hansman

Hanisch

et al. 2018

Molecular Nutrition Food Res

Self Cite

104

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“…3) might exert additional influence on the efficiency with which Saga-2006 and NSW-2012 VLPs bind to HBGAs present in PGM. Indeed, a similar kind of varied level of HBGA binding and inhibition was also observed with genetically related GII.4 noroviruses isolated from a chronically infected individual (33).…”

Section: Resultssupporting

confidence: 55%

Human Norovirus Neutralized by a Monoclonal Antibody Targeting the HBGA Pocket

Koromyslova

Morozov

Hefele

et al. 2018

Preprint

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22Temporal changes in the GII.4 human norovirus capsid sequences occasionally result 23 in the emergence of genetic variants capable of causing new epidemics. The GII.4 24 persistence is believed to be associated with the recognition of numerous histo-blood 25 group antigen (HBGA) types and antigenic drift. We found that one of the earliest 26 known GII.4 isolate (1974) and a more recent epidemic GII.4 variant (2012) had 27 varied norovirus-specific monoclonal antibody (MAb) reactivities, yet similar HBGA 28 binding profiles. To better understand the binding interaction of one MAb (10E9) that 29 had varied reactivities with these GII.4 variants, we determined the X-ray crystal 30 structure of the NSW-2012 GII.4 P domain 10E9 Fab complex. We showed that the 31 10E9 Fab interacted with conserved and variable residues, which could be associated 32 with antigenic drift. Interestingly, the 10E9 Fab binding pocket partially overlapped 33 the HBGA pocket and had direct competition for conserved HBGA binding residues 34 (i.e., Arg345 and Tyr444). Indeed, the 10E9 MAb blocked norovirus VLPs from 35 binding to several sources of HBGAs. Moreover, the 10E9 antibody completely 36 abolished virus replication in the human norovirus intestinal enteroid cell culture 37 system. Our new findings provide first direct evidence that competition for GII.4 38 HBGA binding residues and steric obstruction could lead to norovirus neutralization. 39On the other hand, the 10E9 MAb recognized residues flanking the HBGA pocket, 40 which are often substituted as the virus evolves. This mechanism of antigenic drift 41 likely influences herd immunity and impedes the possibility of acquiring broadly 42 reactive HBGA-blocking antibodies. 43 3 IMPORTANCE 44 45

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“…To begin to evaluate HuNoV infection, we showed that HuNoV RNAs are present within Vero cells following a 1 h or 6 h incubation by qRT-PCR ( Figure 1A). HuNoVs use HBGAs, such as the H-antigen, as attachment factors [55][56][57]; however, they are not a requirement for HuNoV infection [58][59][60][61][62]. We examined the level of H-antigen expression on Vero cells or Caco-2 cells and showed that Vero cells do not express the H-antigen by ELISA ( Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

Todd

Tripp

2020

Viruses

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Human norovirus (HuNoV) is a principal cause of acute gastroenteritis worldwide, particularly in developing countries. Its global prevalence is underscored by more serious morbidity and some mortality in the young (<5 years) and the elderly. To date, there are no licensed vaccines or approved therapeutics for HuNoV, mostly because there are limited cell culture systems and small animal models available. Recently described cell culture systems are not ideal substrates for HuNoV vaccine development because they are not clonal or only support a single strain. In this study, we show Vero cell-based replication of two pandemic GII.4 HuNoV strains and one GII.3 strain and confirm exosome-mediated HuNoV infection in Vero cells. Lastly, we show that trypsin addition to virus cultures or disruption of Vero cell host genes can modestly increase HuNoV replication. These data provide support for Vero cells as a cell culture model for HuNoV.

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Human Norovirus Evolution in a Chronically Infected Host

Cited by 29 publications

References 48 publications

Human Milk Oligosaccharides as Promising Antivirals

Human Milk Oligosaccharides as Promising Antivirals

Human Norovirus Neutralized by a Monoclonal Antibody Targeting the HBGA Pocket

Vero Cells as a Mammalian Cell Substrate for Human Norovirus

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