Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages

Wobus, Christiane E.; Karst, Stephanie M.; Thackray, Larissa B.; Chang, Kyung-Ro; Sosnovtsev, Stanislav V.; Belliot, Gaël; Krug, Anne; Mackenzie, Jason M.; Green, Kim Y.; Virgin, Herbert W.

doi:10.1371/journal.pbio.0020432

Cited by 747 publications

(985 citation statements)

References 33 publications

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“…The TEM images showed cells with morphological changes and the presence of viral particles similar to what has been described for murine NoV 1 infection of macrophages in vitro (53). Contrary to what has been described for infection of epithelial cells in cats by FCV (35), which belongs to the Vesivirus genus, no viral particles were observed in the nucleus.…”

Section: Discussionsupporting

confidence: 75%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

257

264

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Human noroviruses (HuNoVs) are a major cause of foodborne gastroenteritis worldwide. Because they do not grow in cell culture and there is no animal model for HuNoVs, pathogenesis studies have been hampered. Thus, little is known about their replication strategies or induction of neutralizing antibodies.The limited information on their pathogenesis is from human volunteer studies of HuNoV infections in which villus atrophy in duodenal biopsies and presence of malabsorptive diarrhea were described (1,7,8). No information is available on lesions in other portions of the intestines of these volunteers (9). Intestinal transplant pediatric patients that were diagnosed with HuNoV infection developed secretory or osmotic diarrhea (19,20,31). These patients had prolonged diarrhea (17 to 326 days) due to immunosuppressive therapy. The detection of HuNoV RNA and the clinical symptoms remitted after reduction of the immunosuppressive therapy. Usually in exposed individuals, histologic lesions correlate with diarrhea, but in one report, lesions in volunteers who did not show clinical symptoms were described (42). There are also numerous reports of asymptomatic individuals who were infected with HuNoVs and shed virus in the feces (11, 28).Most past attempts to study these viruses in an animal model may have failed because (i) the human strains that were used were not closely related to the host animal NoV strains, (ii) sensitive detection techniques were lacking, and finally (iii) the role of histo-blood group antigen (HBGA) phenotypes in differential susceptibility of the host was unrecognized. Our goal was to adapt a HuNoV strain to replicate in the gnotobiotic (Gn) pig to develop an animal model for the study of HuNoV pathogenesis. Gnotobiotic pigs are good models for human enteric diseases (40) because pigs resemble humans in their gastrointestinal anatomy, physiology, and immune responses. The Gn pigs are immunocompetent at birth, but they lack maternal antibodies and previous or ongoing exposure to microbial agents, including caliciviruses.Recently, viral RNA genetically similar to that of human NoV GII (65 to 71% amino acid sequence identity in the capsid gene) was detected in pigs in Japan (46, 47) and Europe (22,48). In U.S. swine, our laboratory detected both viral RNA and virus particles similar to GII HuNoV (70% sequence identity in the capsid region) which were infectious for Gn pigs (50). Our approach to infect Gn pigs with a HuNoV was to use a GII strain that is closely related genetically to the identified GII porcine NoVs and that has a broad HBGA binding pattern because little information or reagents are available for pig HBGA. Additionally, we used sensitive assays and reagents including reverse transcription (RT)-PCR to detect fecal shedding, virus-like particles (VLPs) for serological assays, and antisera to these VLPs for antigen enzyme-linked immunosor-

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Section: Discussionsupporting

confidence: 75%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

257

264

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“…The porcine SaV Cowden strain was adapted to growth in a continuous porcine kidney cell line [31,32] and bile acids and a signal transduction pathway was shown to influence its replication in vitro and potentially in vivo in the duodenum [33]. The murine NoV MNV-1 strain was subsequently shown to replicate in primary murine dendritic cells and macrophages [34]. The Cowden and MNV-1 strains remain the only cultivable SaV and NoV strains, respectively, in the world.…”

Section: History Of Enteric Caliciviruses and The Discovery Of Pormentioning

confidence: 99%

“…The detection of an RNA molecule of ~2 kb in stool samples from a human volunteer infected with NoV Norwalk strain and detection of a 2.3 kb RNA from murine NoV MNV-1-infected RAW 264.7 cells strongly suggests that NoVs produce subgenomic RNA molecules [25,34]. Similarly, a 2.2 kb RNA was detected by an in vitro replication assay with the replication complex of SaV Cowden strain extracted from virus-infected cells suggesting that SaVs also generate subgenomic RNA during virus replication [33].…”

Section: Recombination Of Porcine Novs and Savsmentioning

confidence: 99%

Porcine enteric caliciviruses: Genetic and antigenic relatedness to human caliciviruses, diagnosis and epidemiology

Wang

Costantini

Saif

2007

Vaccine

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Porcine enteric caliciviruses include sapoviruses and noroviruses. Porcine sapoviruses infect pigs of all ages and cause diarrhea in young pigs, whereas porcine noroviruses were detected exclusively from adult pigs without clinical signs. Importantly, certain porcine norovirus strains were genetically and antigenically related to human noroviruses. This raises public health concerns that pigs may be reservoirs for emergence of epidemic human norovirus strains. This article reviews the discovery of porcine noroviruses and sapoviruses, their classification, diagnosis, epidemiology and genetic and antigenic relatedness to human caliciviruses.

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“…Since the discovery of the first HuNoV over 40 y ago by Kapikian et al, 11 extensive efforts have been undertaken to culture these viruses Keywords: enteric virus, histo-blood group antigen, intestinal microbiota, norovirus in epithelial cells including IECs but thus far no published and reproducible data support infection of this cell type in vitro. 12 Murine NoVs (MuNoVs) efficiently and lytically replicate in macrophages and dendritic cells 13 but efforts to infect these cell types with HuNoVs in culture have been unsuccessful. 14 Several observations by our lab and other research groups led us to speculate that B cells represent another NoV target.…”

Section: Introductionmentioning

confidence: 99%

Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages

Cited by 747 publications

References 33 publications

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Porcine enteric caliciviruses: Genetic and antigenic relatedness to human caliciviruses, diagnosis and epidemiology

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

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