Rotavirus antigenaemia and viraemia: a common event?

Blutt, Sarah E.; Kirkwood, Carl D.; Parreño, Viviana; Warfield, Kelly L.; Ciarlet, Max; Estes, Mary K.; Bok, Karin; Bishop, Ruth F.; Conner, Margaret E.

doi:10.1016/s0140-6736(03)14687-9

Cited by 223 publications

(206 citation statements)

References 19 publications

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“…Similar percentages of viremia were detected in P0-, P1-, and P2-inoculated pigs in a more extensive study (Souza, Cheetham, and Saif, unpublished). Viremia has been detected for other enteric viruses such as the porcine sapoviruses (PEC/Cowden) in pigs and human rotavirus in humans, mice, and pigs without causing lesions outside the small intestines (4,5,14). As described for PEC/Cowden (14), we report that one pig inoculated intravenously with P0 showed viral shedding and diarrhea.…”

Section: Discussionsupporting

confidence: 60%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

250

260

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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: 60%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

J Virol

250

260

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“…Although such immune cell recruitment in response to rotavirus occurs on a much smaller scale than that seen in response to bacterial pathogens (e.g., Salmonella, Shigella) (9), the fact that rotavirus infection is localized generally to the gastrointestinal tract suggests that, nonetheless, rotaviral-induced immune cell recruitment may be important for preventing viral spread throughout the host. Rotavirus indeed has the potential to infect extraintestinal sites as rotaviral RNA has been found in cerebral spinal fluid and serum of some rotavirus-infected children, possibly associated antigenemia and viremia (10). In addition to a potential role in impeding viral dissemination, epithelial gene expression in response to rotavirus may also be important for regulating the adaptive immune response analogous to processes thought to occur in response to bacterial colonization of epithelia.…”

mentioning

confidence: 99%

Protein Kinase R Mediates Intestinal Epithelial Gene Remodeling in Response to Double-Stranded RNA and Live Rotavirus

Vijay‐Kumar

Gentsch

Kaiser

et al. 2005

The Journal of Immunology

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As sentinels of host defense, intestinal epithelial cells respond to the viral pathogen rotavirus by activating a gene expression that promotes immune cell recruitment and activation. We hypothesized that epithelial sensing of rotavirus might target dsRNA, which can be detected by TLR3 or protein kinase R (PKR). Accordingly, we observed that synthetic dsRNA, polyinosinic acid:cytidylic acid (poly(I:C)), potently induced gene remodeling in model intestinal epithelia with the specific pattern of expressed genes, including both classic proinflammatory genes (e.g., IL-8), as well as genes that are classically activated in virus-infected cells (e.g., IFN-responsive genes). Poly(I:C)-induced IL-8 was concentration dependent (2–100 μg/ml) and displayed slower kinetics compared with IL-8 induced by bacterial flagellin (ET50 ∼24 vs 8 h poly(I:C) vs flagellin, respectively). Although model epithelia expressed detectable TLR3 mRNA, neither TLR3-neutralizing Abs nor chloroquine, which blocks activation of intracellular TLR3, attenuated epithelial responses to poly(I:C). Conversely, poly(I:C)-induced phosphorylation of PKR and inhibitors of PKR, 2-aminopurine and adenine, ablated poly(I:C)-induced gene expression but had no effect on gene expression induced by flagellin, thus suggesting that intestinal epithelial cell detection of dsRNA relies on PKR. Consistent with poly(I:C) detection by an intracellular molecule such as PKR, we observed that both uptake of and responses to poly(I:C) were polarized to the basolateral side. Lastly, we observed that the pattern of pharmacologic inhibition of responses to poly(I:C) was identical to that seen in response to infection by live rotavirus, indicating a potentially important role for PKR in activating intestinal epithelial gene expression in rotavirus infection.

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“…Animal studies support these observations. Rotavirus and/or rotavirus antigen was recovered from the blood, liver, spleen, kidneys, lungs, and mesenteric lymph nodes (MLN) of orally inoculated mice (1,2,4,10,16,27), and mouse models for rotavirusinduced hepatitis (29) and biliary atresia (25) were previously described.…”

mentioning

confidence: 99%

A Lymphatic Mechanism of Rotavirus Extraintestinal Spread in the Neonatal Mouse

Mossel

Ramig

2003

J Virol

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We used the neonatal mouse model of rotavirus infection and virus strains SA11-clone 4 (SA11-Cl4) and Rhesus rotavirus (RRV) to examine the mechanism of the extraintestinal spread of viruses following oral inoculation. The spread-competent viruses, RRV and reassortant R7, demonstrated a temporal progression from the intestine, to the terminal ileum, to the mesenteric lymph nodes (MLN), and to the peripheral tissues. SA11-Cl4 was not found outside the intestine. Reassortant virus S7, which was unable to reach the liver in previous studies (E. C. Mossel and R. F. Ramig, J. Virol. 76:6502-6509, 2002), was recovered from 60% of the MLN, suggesting that there are multiple determinants for the spread of virus from the intestine to the MLN. Phenotypic segregation analysis identified RRV genome segment 6 (VP6) as a secondary determinant of the spread of virus to the MLN (P ‫؍‬ 0.02) in reassortant viruses containing segment 7 from the spreadincompetent parent. These data suggest that in the orally infected neonatal mouse, the extraintestinal spread of rotavirus occurs via a lymphatic pathway, and the spread phenotype is primarily determined by NSP3 and can be modified by VP6.

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Rotavirus antigenaemia and viraemia: a common event?

Cited by 223 publications

References 19 publications

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Protein Kinase R Mediates Intestinal Epithelial Gene Remodeling in Response to Double-Stranded RNA and Live Rotavirus

A Lymphatic Mechanism of Rotavirus Extraintestinal Spread in the Neonatal Mouse

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