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Li JT, Wei J, Guo HX, Han JB, Ye N, He HY, Yu TT, Wu YZ. Development of a human rotavirus induced diarrhea model in Chinese mini-pigs. World J Gastroenterol 2016; 22:7135-7145. [PMID: 27610023 PMCID: PMC4988310 DOI: 10.3748/wjg.v22.i31.7135] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/26/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a new animal model for the research of human rotavirus (HRV) infection, its pathogenesis and immunity and evaluation of potential vaccines.
METHODS: 5-d, 30-d and 60-d-old Chinese mini-pigs, Guizhou and Bamma, were inoculated with a single oral dose of attenuated strain Wa, G1, G3 of HRV, and PBS (control), respectively, and fecal samples of pigs from 0 to 7 d post infection (DPI) were collected individually. Enzyme linked immunosorbent assay was used to detect HRV antigen in feces. The HRV was tested by real-time PCR (RT-PCR). The sections of the intestinal tissue were stained with hematoxylin and eosin to observe the morphologic variation by microscopy. Immunofluorescence was used to determine the HRV in intestinal tissue. HRV particles in cells of the ileum were observed by electron micrography.
RESULTS: When inoculated with HRV, mini-pigs younger than 30 d developed diarrhea in an age-dependent manner and shed HRV antigen of the same inoculum, as demonstrated by RT-PCR. Histopathological changes were observed in HRV inoculated mini-pigs including small intestinal cell tumefaction and necrosis. HRV that was distributed in the small intestine was restricted to the top part of the villi on the internal wall of the ileum, which was observed by immunofluorescence and transmission electron microscopy. Virus particles were observed in Golgi like follicles in HRV-infected neonatal mini-pigs. Guizhou mini-pigs were more sensitive to HRV than Bamma with respect to RV antigen shedding and clinical diarrhea.
CONCLUSION: These results indicate that we have established a mini-pig model of HRV induced diarrhea. Our findings are useful for the understanding of the pathogenic mechanisms of HRV infection.
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Okadera K, Abe M, Ito N, Mitake H, Okada K, Nakagawa K, Une Y, Tsunemitsu H, Sugiyama M. Isolation and characterization of a novel type of rotavirus species A in sugar gliders (Petaurus breviceps). J Gen Virol 2016; 97:1158-1167. [DOI: 10.1099/jgv.0.000433] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Kota Okadera
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Masako Abe
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Naoto Ito
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
- Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Hiromichi Mitake
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Kazuma Okada
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Kento Nakagawa
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
| | - Yumi Une
- Laboratory of Veterinary Pathology, School of Veterinary Medicine,Azabu University, 1-17-71 Fuchinobe, Kanagawa, 252-5201,Japan
| | - Hiroshi Tsunemitsu
- Dairy Hygiene Research Division, National Institute of Animal Health,4 Hitsujigaoka, Hokkaido, 062-0045,Japan
| | - Makoto Sugiyama
- The United Graduate School of Veterinary Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
- Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences,Gifu University, 1-1 Yanagido, Gifu 501-1193,Japan
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3
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Characterization of a novel G3P[3] rotavirus isolated from a lesser horseshoe bat: a distant relative of feline/canine rotaviruses. J Virol 2013; 87:12357-66. [PMID: 24027312 DOI: 10.1128/jvi.02013-13] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Bats are considered important animal reservoirs for many viruses pathogenic to humans. An approach based on viral metagenomics was used to study gut specimens from 78 insectivorous bats in Yunnan Province, China. Seventy-four reads were found to be related to group A rotavirus (RVA). Further reverse transcription-PCR screening and viral isolation on cell cultures confirmed the presence of a novel RVA strain, named RVA/Bat-tc/MSLH14/2012/G3P[3], in 1 (6%) of 16 lesser horseshoe bats. Full genomic sequencing analyses showed that MSLH14 possessed the genotype constellation G3-P[3]-I8-R3-C3-M3-A9-N3-T3-E3-H6, which is akin to human and animal rotaviruses believed to be of feline/canine origin. Phylogenetic analysis indicated that VP7 was most closely related to bovine RVA strains from India, whereas VP4 was most closely related to an unusual human RVA strain, CMH222, with animal characteristics isolated in Thailand. The remaining gene segments were only distantly related to a range of animal RVA strains, most of which are believed to be related to feline/canine RVAs. Experimental infection showed that bat RVA strain MSLH14 was highly pathogenic to suckling mice, causing 100% mortality when they were inoculated orally with a titer as low as 5 × 10² 50% tissue culture infective doses. As this virus is not closely related to any known RVA strain, it is tempting to speculate that it is a true bat RVA strain rather than a virus transmitted between species. However, further screening of bat populations, preferably juvenile animals, will be crucial in determining whether or not this virus is widely distributed in the bat population.
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Buragohain M, S. Dhale G, R. Ghalsasi G, D. Chitambar S. Evaluation of Hyperimmune Hen Egg Yolk Derived Anti-Human Rotavirus Antibodies (Anti-HRVIgY) against Rotavirus Infection. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/wjv.2012.22010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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5
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Buragohain M, Dhale GS, Raut CG, Kang G, Chitambar SD. Analyses of clinical, pathological and virological features of human rotavirus strain, YO induced gastroenteritis in infant BALB/c mice. Microbes Infect 2010; 13:331-8. [PMID: 21163362 DOI: 10.1016/j.micinf.2010.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Accepted: 12/06/2010] [Indexed: 10/18/2022]
Abstract
Experimental studies of human rotavirus infections in mice are limited and there is lack of information on the quantitative assessment of rotaviral replication and its relationship with histological changes. In the present study, consequences of human rotavirus strain, YO induced gastroenteritis in infant BALB/c mice were analyzed for the occurrence of clinical symptoms, histopathology and virological events. The infected animals developed diarrhea and dehydration and showed accumulation of vacuolated enterocytes with lodging of the rotavirus antigens and shortening of villi in the intestine over a period of 5 days. The ileum was identified as the most susceptible and supportive part of small intestine for perpetuation of rotavirus infection in mice. Rotaviral antigen/RNA in stool and RNA in intestine were detected throughout the clinical disease period. At 48-72 h post inoculation, diarrhea was at the peak (90-95%) in the infected animals with increased load of viral RNA and intense pathological lesions suggesting it as the critical time point in the course of infection. The rising titers of antirotavirus neutralizing antibodies ascertained the replication of human rotavirus strain, YO in mice. These data may contribute to the understanding of pathophysiological, immunological and virological characteristics of rotavirus infections in mice.
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Affiliation(s)
- Manika Buragohain
- Enteric Viruses Department, National Institute of Virology, 20-A, Dr. Ambedkar Road, Pune - 411 001, India
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6
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Reimerink JHJ, Boshuizen JA, Einerhand AWC, Duizer E, van Amerongen G, Schmidt N, Koopmans MPG. Systemic immune response after rotavirus inoculation of neonatal mice depends on source and level of purification of the virus: implications for the use of heterologous vaccine candidates. J Gen Virol 2007; 88:604-612. [PMID: 17251579 DOI: 10.1099/vir.0.82126-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Rotavirus is an important cause of morbidity and mortality worldwide and vaccines are currently under development, with clinical trails conducted in humans worldwide. The immune responses in infant BALB/c mice were examined following oral inoculation with murine rotavirus EDIM (2 x 10(4) focus-forming units) and with three CsCl gradient-purified fractions of heterologous simian rotavirus SA11 (standardized at 2 x 10(6) CCID(50)) that differed in antigen composition: fraction 1 was enriched for double-layered rotavirus particles, fraction 2 for triple-layered particles and fraction 3 consisted mainly of cell components. Diarrhoea and high IgG responses, but marginal IgA responses, were observed after inoculation with all three SA11 fractions. Virus shedding was observed in all EDIM-inoculated mice, but in none of the SA11-inoculated mice. Rotavirus-specific IgG1 : 2a ratios were similar in mice inoculated with EDIM and SA11 fraction 1, but higher for SA11 fraction 3- and lower for SA11 fraction 2-inoculated mice. A higher IgG1 : 2a ratio indicates a more Th2-like immune response. This undesirable response is apparently mostly induced by inoculation with heterologous rotavirus in the presence of abundant cell-associated and soluble rotavirus proteins, compared with infection with a more purified preparation or with homologous virus. These data show that, following inoculation with a standardized amount of infectious virus, the composition of the fraction influences the outcome of the immune responses significantly.
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Affiliation(s)
- Johan H J Reimerink
- Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), The Netherlands
| | - Jos A Boshuizen
- Laboratory of Pediatrics, Pediatric Gastroenterology and Nutrition, Erasmus MC/Sophia, Rotterdam, The Netherlands
| | - Alexandra W C Einerhand
- Laboratory of Pediatrics, Pediatric Gastroenterology and Nutrition, Erasmus MC/Sophia, Rotterdam, The Netherlands
| | - Erwin Duizer
- Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), The Netherlands
| | - Geert van Amerongen
- Central Animal Laboratory, National Institute for Public Health and the Environment (RIVM), The Netherlands
| | - Nico Schmidt
- Central Animal Laboratory, National Institute for Public Health and the Environment (RIVM), The Netherlands
| | - Marion P G Koopmans
- Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), The Netherlands
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7
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Boshuizen JA, Reimerink JHJ, Korteland-van Male AM, van Ham VJJ, Koopmans MPG, Büller HA, Dekker J, Einerhand AWC. Changes in small intestinal homeostasis, morphology, and gene expression during rotavirus infection of infant mice. J Virol 2004; 77:13005-16. [PMID: 14645557 PMCID: PMC296055 DOI: 10.1128/jvi.77.24.13005-13016.2003] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Rotavirus is the most important cause of infantile gastroenteritis. Since in vivo mucosal responses to a rotavirus infection thus far have not been extensively studied, we related viral replication in the murine small intestine to alterations in mucosal structure, epithelial cell homeostasis, cellular kinetics, and differentiation. Seven-day-old suckling BALB/c mice were inoculated with 2 x 10(4) focus-forming units of murine rotavirus and were compared to mock-infected controls. Diarrheal illness and viral shedding were recorded, and small intestinal tissue was evaluated for rotavirus (NSP4 and structural proteins)- and enterocyte-specific (lactase, SGLT1, and L-FABP) mRNA and protein expression. Morphology, apoptosis, proliferation, and migration were evaluated (immuno)histochemically. Diarrhea was observed from days 1 to 5 postinfection, and viral shedding was observed from days 1 to 10. Two peaks of rotavirus replication were observed at 1 and 4 days postinfection. Histological changes were characterized by the accumulation of vacuolated enterocytes. Strikingly, the number of vacuolated cells exceeded the number of cells in which viral replication was detectable. Apoptosis and proliferation were increased from days 1 to 7, resulting in villous atrophy. Epithelial cell turnover was significantly higher (<4 days) than that observed in controls (7 days). Since epithelial renewal occurred within 4 days, the second peak of viral replication was most likely caused by infection of newly synthesized cells. Expression of enterocyte-specific genes was downregulated in infected cells at mRNA and protein levels starting as early as 6 h after infection. In conclusion, we show for the first time that rotavirus infection induces apoptosis in vivo, an increase in epithelial cell turnover, and a shutoff of gene expression in enterocytes showing viral replication. The shutoff of enterocyte-specific gene expression, together with the loss of mature enterocytes through apoptosis and the replacement of these cells by less differentiated dividing cells, likely leads to a defective absorptive function of the intestinal epithelium, which contributes to rotavirus pathogenesis.
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Affiliation(s)
- Jos A Boshuizen
- Laboratoryof Pediatrics, Pediatric Gastroenterology, and Nutrition, Erasmus MC/ Sophia, Rotterdam, The Netherlands
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8
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Mori Y, Borgan MA, Takayama M, Ito N, Sugiyama M, Minamoto N. Roles of outer capsid proteins as determinants of pathogenicity and host range restriction of avian rotaviruses in a suckling mouse model. Virology 2003; 316:126-34. [PMID: 14599797 DOI: 10.1016/j.virol.2003.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
We previously demonstrated that a pigeon rotavirus, PO-13, but not turkey strains Ty-3 and Ty-1 and a chicken strain, Ch-1, induced diarrhea in heterologous suckling mice. In this study, it was suggested that these avirulent strains, but not PO-13, were inactivated immediately in gastrointestinal tracts of suckling mice when they were orally inoculated. To determine which viral proteins contribute to the differences between the pathogenicitiy and the inactivation of PO-13 and Ty-3 in suckling mice, six PO-13 x Ty-3 reassortant strains that had the genes of the outer capsid proteins, VP4 and VP7, derived from the opposite strain were prepared and were orally inoculated to suckling mice. A single strain that had both PO-13 VP4 and VP7 with the genetic background of Ty-3 had an intermediate virulence for suckling mice. Three strains with Ty-3 VP7, regardless of the origin of VP4, rapidly disappeared from gastrointestinal tracts of suckling mice. These results indicated that the difference between the pathogenicity of PO-13 and that of Ty-3 was mainly dependent on both their VP4 and VP7. In particular, VP7 was found to be related to the inactivation of Ty-3 in gastrointestinal tracts of suckling mice.
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Affiliation(s)
- Yoshio Mori
- Laboratory of Zoonotic Diseases, Division of Veterinary Medicine, Faculty of Agriculture, Gifu University, 1-1 Yanagido, 501-1193, Gifu, Japan
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9
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Ciarlet M, Hyser JM, Estes MK. Sequence analysis of the VP4, VP6, VP7, and NSP4 gene products of the bovine rotavirus WC3. Virus Genes 2002; 24:107-18. [PMID: 12018701 DOI: 10.1023/a:1014512314545] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The bovine rotavirus (BRV) WC3 serves as the background strain in the development of a multivalent reassortant vaccine against rotavirus gastroenteritis in infants. The genes encoding the outer capsid spike protein VP4, the inner capsid protein VP6, the outer capsid glycoprotein VP7, and the viral enterotoxin NSP4 of BRV WC3 were sequenced. Comparative analysis of the deduced amino acids of the sequenced genes indicated that the BRV WC3 strain shares a high degree of amino acid identity with serotype P7 VP4 (93-96%), serotype G6 VP7 (91-97%), subgroup (SG) I VP6 (96-99%), and NSP4 genogroup A (96-98%) BRV strains. Our results confirm and extend previous studies which suggested that the VP4 of BRV WC3 was closely related to that of the P7 prototype, BRV UK. In addition, the VP6 and VP7 of BRV WC3 were very similar to the VP6 and VP7 of both SG I and G6 BRV NCDV and UK strains. However, the NSP4 of BRV WC3 was more closely related to that BRV NCDV, the P6 prototype, than to that of BRV UK.
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Affiliation(s)
- Max Ciarlet
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
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10
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He ST, He FZ, Wu CR, Li SX, Liu WX, Yang YF, Jiang SS, He G. Treatment of rotaviral gastroenteritis with Qiwei Baizhu powder. World J Gastroenterol 2001; 7:735-40. [PMID: 11819866 PMCID: PMC4695586 DOI: 10.3748/wjg.v7.i5.735] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the effects of Qiwei Baizhu Powder (QWBZP) on rotaviral gastroenteritis in children and in animal models.
METHODS: Enrolled patients were divided into two groups, and one group was treated with oral rehydration solution (ORS) and the other treated with oral liquid of QWBZP. Neonate mice were orally infected with 50 μL rotavirus suspension (4 × 108 PFU/mL) and treated with ORS or oral liquid of QWBZP, respectively.
RESULTS: Eighty-three cases of rotaviral gastroenteritis treated with QWBZP revealed a better efficacy than that treated with ORS (χ² = 10.87, P ＜ 0.05). The contents of sodium and glucose as well as number of patients with positive human rotavirus antigen in stool in QWBZP group were all less than that in ORS group. In animal models, QWBZP was found effective in treating rotavirus gastroenteritis in neonate NIH mice, as compared with control groups. In QWBZP group, the mortality of infected mice was decreased by 73.3%, the body weight of infected mice was increased, the contents of sodium and glucose as well as number of mice with positive rotavirus antigen in feces were significantly reduced, and the pathological changes such as damage of small intestinal mucosa and villi were also obviously alleviated.
CONCLUSION: QWBZP has effects on improving the absorptive function of small intestine, shortening the duration of diarrhea and rotavirus shedding from stool and alleviating the pathological changes of small intestine induced by rotavirus.
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Affiliation(s)
- S T He
- Institute of Combined Traditional Chinese and Western Medicine, Xiangya Hospital, Hunan Medical University, Changsha 410008, Hunan Province, China.
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11
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Mori Y, Sugiyama M, Takayama M, Atoji Y, Masegi T, Minamoto N. Avian-to-mammal transmission of an avian rotavirus: analysis of its pathogenicity in a heterologous mouse model. Virology 2001; 288:63-70. [PMID: 11543658 DOI: 10.1006/viro.2001.1051] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It has been suggested that group A avian rotaviruses can be transmitted to mammals, but there is no direct evidence that such viruses induce disease in mammals. Suckling mice were orally inoculated with two avian rotaviruses. A pigeon rotavirus, PO-13, was found to induce diarrhea, but a turkey rotavirus, Ty-3, did not. The diarrhea induced by PO-13 was dependent on the age of the mouse. In histopathological examinations, antigens of PO-13 were sporadically detected in absorptive cells in the ileum, and lesions were observed as ballooning degenerations of absorptive cells in a region from the duodenum to the ileum. However, the rotavirus antigen was not detected in the majority of these degenerative cells. These results indicated that PO-13 could infect and induce diarrhea in suckling mice. This is the first evidence of an avian rotavirus being experimentally transmissible to a mammal.
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Affiliation(s)
- Y Mori
- Department of Veterinary Public Health, Faculty of Agriculture, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
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12
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Guerin-Danan C, Meslin JC, Lambre F, Charpilienne A, Serezat M, Bouley C, Cohen J, Andrieux C. Development of a heterologous model in germfree suckling rats for studies of rotavirus diarrhea. J Virol 1998; 72:9298-302. [PMID: 9765478 PMCID: PMC110350 DOI: 10.1128/jvi.72.11.9298-9302.1998] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Germfree suckling rats were infected with an SA11 rotavirus strain. Infected pups developed diarrhea associated with histopathological changes. The virus was detected in feces and in the small intestine. Cellular vacuolation was observed in the villi of the jejunum. These results provide a new model for further investigations of group A rotavirus infection.
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Affiliation(s)
- C Guerin-Danan
- Unité d'Ecologie et de Physiologie du Système Digestif, Equipe Métabolites Bactériens et Santé, INRA, 78352 Jouy-en-Josas Cedex, France
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13
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Feng N, Franco MA, Greenberg HB. Murine model of rotavirus infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1997; 412:233-40. [PMID: 9192019 DOI: 10.1007/978-1-4899-1828-4_35] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The murine model of homologous rotavirus infection has been used to study the determinants of protection. The local IgA immune response appears to be the critical factor in generating protective immunity after natural infection. A series of knockout mice were used to evaluate the contribution of T cells and B cells to immunity and resolution from primary infection. Both arms of immune system played a role in the resolution of primary infection but antibody was much more important for prevention of reinfection.
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Affiliation(s)
- N Feng
- Department of Microbiology and Immunology, School of Medicine, Stanford University, California 94305, USA
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14
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Khoury CA, Brown KA, Kim JE, Offit PA. Rotavirus-specific intestinal immune response in mice assessed by enzyme-linked immunospot assay and intestinal fragment culture. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY 1994; 1:722-8. [PMID: 8556527 PMCID: PMC368401 DOI: 10.1128/cdli.1.6.722-728.1994] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primate rotavirus strain RRV and bovine strain WC3 or reassortants made between these animal viruses and human rotaviruses have been administered to infants as candidate vaccines. We compared RRV and WC3 in a murine model of oral infection. We determined the relative capacities of these viruses to induce a virus-specific humoral immune response by intestinal lymphocytes as tested by enzyme-linked immunospot assay, intestinal fragment culture, and enzyme-linked immunosorbent assay of intestinal contents. We found that inoculation of mice with RRV induced higher frequencies of virus-specific immunoglobulin A (IgA)-secreting cells in the lamina propria, greater quantities of virus-specific IgA in intestinal fragment cultures, and greater quantities of virus-specific IgA in intestinal secretions than did inoculation with WC3 or inactivated RRV (iRRV). The induction of an IgA response in serum was predictive of an IgA response among intestinal lymphocytes after inoculation with RRV but not WC3. In addition, large quantities of IgG, IgA, and IgM not specific for rotavirus were produced in fragment cultures from mice inoculated with RRV but not in cultures from mice inoculated with WC3 or iRRV. Possible mechanisms of RRV-induced polyclonal stimulation of intestinal B cells are discussed.
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Affiliation(s)
- C A Khoury
- Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine, Philadelphia 19104, USA
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15
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Azuma I, Otani T. Potentiation of host defense mechanism against infection by a cytokine inducer, an acyl-MDP derivative, MDP-Lys(L18) (romurtide) in mice and humans. Med Res Rev 1994; 14:401-14. [PMID: 8084203 DOI: 10.1002/med.2610140403] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- I Azuma
- Institute of Immunological Science, Hokkaido University, Sapporo, Japan
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16
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Affiliation(s)
- H B Greenberg
- Department of Medicine, Stanford University School of Medicine, CA 94305
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17
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Broome RL, Vo PT, Ward RL, Clark HF, Greenberg HB. Murine rotavirus genes encoding outer capsid proteins VP4 and VP7 are not major determinants of host range restriction and virulence. J Virol 1993; 67:2448-55. [PMID: 8386262 PMCID: PMC237563 DOI: 10.1128/jvi.67.5.2448-2455.1993] [Citation(s) in RCA: 85] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Simian rotavirus (RRV) and murine rotavirus (EDIM-RW) differ dramatically in the oral inoculum required to cause diarrheal disease in neonatal mouse pups and in their ability to spread and cause disease in uninoculated littermates. A genetic approach was used to explore the molecular basis of these differences. Reassortant viruses were produced in vivo by coinfecting infant mice with RRV and EDIM-RW. Reassortant viruses were isolated by plaque purification of progeny virus obtained from mouse pup intestines on MA104 cells. The plaque-purified reassortants were evaluated for 50% diarrhea dose (DD50) and for the ability to spread and cause diarrhea in uninoculated littermates. The parental RRV strain had a DD50 of 10(5) PFU per animal, while the EDIM-RW parental strain had a DD50 of less than 1 PFU per animal. RRV never spreads from inoculated to uninoculated littermates and causes disease. Twenty-three reassortants were tested. Of great interest were the reassortants D1/5 and C3/2, which derived genes 4 and 7 (encoding VP4 and VP7) from RRV. These viruses had a DD50 similar or identical to that of EDIM-RW and spread efficiently from inoculated mouse pups to uninoculated pups. We conclude that the major outer capsid proteins VP4 and VP7 are not primarily responsible for virulence or host range restriction in the mouse model using a homologous murine rotavirus.
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Affiliation(s)
- R L Broome
- Veterinary Medical Unit, Veterans Affairs Medical Center, Palo Alto, California 94304
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18
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Uhnoo I, Riepenhoff-Talty M, Chegas P, Fisher JE, Greenberg HB, Ogra PL. Effect of malnutrition on extraintestinal spread of rotavirus and development of hepatitis in mice. Nutr Res 1990. [DOI: 10.1016/s0271-5317(05)80134-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Ward RL, McNeal MM, Sheridan JF. Development of an adult mouse model for studies on protection against rotavirus. J Virol 1990; 64:5070-5. [PMID: 2168987 PMCID: PMC247999 DOI: 10.1128/jvi.64.10.5070-5075.1990] [Citation(s) in RCA: 110] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Although mice have been used as an animal model for studies on rotavirus disease, these studies have been limited by the short time period after birth during which mice are susceptible to rotavirus illness (i.e., approximately 15 days). To overcome this limitation, an adult mouse model was developed in which the endpoint was infection rather than illness. The model developed utilized a strain of mouse rotavirus (EDIM) adapted to grow in culture by multiple passages in MA104 cells. The second cell culture passage of EDIM caused severe diarrhea in neonatal BALB/c mice, and little or no amelioration of disease was observed after nine cell culture passages, even when this preparation was plaque purified. Oral administration of 2 x 10(3) PFU of passage 9 also consistently caused infection of mice 4, 10, 15, 30, 60, 120, and 180 days of age as determined by viral shedding and seroconversion. Reinoculation of these mice with the same virus preparation at 2, 3, or 4 months after the first inoculation produced no evidence of reinfection. In contrast, infection of neonatal mice with the heterotypic WC3 bovine rotavirus did not prevent reinfection with culture-adapted EDIM. Thus, this strain of EDIM caused consistent infection of previously uninoculated neonatal and adult BALB/c mice and produced homotypic but not heterotypic protection against reinfection.
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Affiliation(s)
- R L Ward
- James N. Gamble Institute of Medical Research, Cincinnati, Ohio 45219
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Ebina T, Tsukada K, Umezu K, Nose M, Tsuda K, Hatta H, Kim M, Yamamoto T. Gastroenteritis in suckling mice caused by human rotavirus can be prevented with egg yolk immunoglobulin (IgY) and treated with a protein-bound polysaccharide preparation (PSK). Microbiol Immunol 1990; 34:617-29. [PMID: 2176268 DOI: 10.1111/j.1348-0421.1990.tb01037.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Oral inoculation of human rotavirus MO strain (serotype 3) into 5-day-old BALB/c mice cause gastroenteritis characterized by diarrhea. Clinical symptoms, histopathological changes in the small intestine, and the detection of rotavirus antigen in enterocytes were all characteristic of rotavirus-induced gastroenteritis. Using this small animal model, passive protection of suckling mice against human rotavirus infection was achieved with the use of immunoglobulin (IgY) from the yolks of eggs of rotavirus-immunized hens. When IgY against a rotavirus strain homotypic to the challenge virus (MO strain) was administered in the mice, complete protection against rotavirus infection was achieved. On the other hand, with oral administration of IgY against a heterotypic strain (serotype 1, Wa strain), a lower protective effect was nevertheless obtained. The four different strains of human rotavirus (Wa, KUN, MO, and ST3) were inactivated in vitro by treatment with PSK, a protein-bound polysaccharide preparation, in a dose-dependent manner. Oral administration of 2.5 mg of PSK caused a therapeutic effect on experimentally MO-infected suckling mice. The antiviral effect of PSK was indicated by the reduction of the duration of diarrhea.
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Affiliation(s)
- T Ebina
- Department of Bacteriology, Tohoku University School of Medicine, Miyagi
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21
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Uhnoo I, Riepenhoff-Talty M, Dharakul T, Chegas P, Fisher JE, Greenberg HB, Ogra PL. Extramucosal spread and development of hepatitis in immunodeficient and normal mice infected with rhesus rotavirus. J Virol 1990; 64:361-8. [PMID: 2152822 PMCID: PMC249110 DOI: 10.1128/jvi.64.1.361-368.1990] [Citation(s) in RCA: 77] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The pathogenic profiles of two heterologous animal rotaviruses, rhesus rotavirus strain MMU 18006 and bovine rotavirus strain WC3, were evaluated in mice with severe combined immunodeficiency (SCID mice) and normal BALB/c mice. Control animals were inoculated with homologous murine strain EDIM 5099 or a tissue culture-adapted murine rotavirus. Heterologous infection with rhesus rotavirus resulted in hepatitis in 84% of SCID and 21% of BALB/c mice, with mortality rates of 27 and 0%, respectively. Surviving SCID animals developed chronic liver disease, while symptoms in BALB/c mice resolved in 2 to 4 weeks after onset. Histopathologic examination revealed a diffuse hepatitis with focal areas of parenchymal necrosis. Rotavirus was detected in liver tissue from 100% of 29 SCID and 85% (11 of 13) BALB/c animals tested by cell culture infectivity, immunofluorescence, or electron microscopy. No extramucosal spread of virus or hepatitis was observed after infection with heterologous bovine strain WC3 or homologous murine rotaviruses. This finding of a novel rotavirus-induced disease manifestation suggests altered tissue tropism in a heterologous host for a group of viruses previously shown to replicate exclusively in the gut mucosa. The implications of our observations suggest that in human vaccine trials utilizing heterologous rotavirus strains, special attention should be paid to children with immunodeficiency disorders, and screening for hepatic function should be included in vaccine protocols.
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Affiliation(s)
- I Uhnoo
- Department of Pediatrics, School of Medicine, State University of New York, Buffalo
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22
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Pongsuwanne Y, Taniguchi K, Choonthanom M, Chiwakul M, Susansook T, Saguanwongse S, Jayavasu C, Urasawa S. Subgroup and serotype distributions of human, bovine, and porcine rotavirus in Thailand. J Clin Microbiol 1989; 27:1956-60. [PMID: 2550515 PMCID: PMC267717 DOI: 10.1128/jcm.27.9.1956-1960.1989] [Citation(s) in RCA: 32] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The subgroup and serotype specificities of human, bovine, and porcine group A rotaviruses in stool specimens collected in Thailand were examined by an enzyme-linked immunosorbent assay by using subgroup- and serotype-specific monoclonal antibodies. A clear yearly change was observed in the serotype distribution of human rotavirus. Between 1983 and 1984, serotype 4 was the most prevalent, while the highest frequency of serotype 2 was found between 1987 and 1988. All the bovine and porcine rotaviruses examined showed subgroup I specificities and long RNA patterns. It was of note that serotype 3 porcine rotaviruses were found at a high frequency.
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Affiliation(s)
- Y Pongsuwanne
- Department of Medical Science, National Institute of Health, Nontaburi, Bangkok, Thailand
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23
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Offit PA, Dudzik KI. Rotavirus-specific cytotoxic T lymphocytes cross-react with target cells infected with different rotavirus serotypes. J Virol 1988; 62:127-31. [PMID: 2824841 PMCID: PMC250510 DOI: 10.1128/jvi.62.1.127-131.1988] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Splenocytes from adult C57BL6 (H-2b) mice orally inoculated with nonmurine rotaviruses lysed syngeneic rotavirus-infected target cells. Cytotoxic T lymphocytes (CTLs) were responsible for this cytotoxic activity. Cytotoxic activity was (i) detected 7 days after primary oral inoculation; (ii) not detected in uninoculated animals; (iii) specific for rotavirus-infected target cells; (iv) eliminated by treatment with Thy 1.2-specific immunoglobulin M and complement; and (v) restricted at H-2Db. In addition, rotavirus-specific CTLs cross-reacted with target cells infected with different human or animal rotavirus serotypes. Heterotypic protection against rotavirus challenge may be mediated by cross-reactive CTLs.
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Affiliation(s)
- P A Offit
- Department of Medical Microbiology, Stanford University School of Medicine, California 94305
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Clark HF, Hoshino Y, Bell LM, Groff J, Hess G, Bachman P, Offit PA. Rotavirus isolate WI61 representing a presumptive new human serotype. J Clin Microbiol 1987; 25:1757-62. [PMID: 2443534 PMCID: PMC269322 DOI: 10.1128/jcm.25.9.1757-1762.1987] [Citation(s) in RCA: 190] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A virus (strain WI61) representing a presumptive new human serotype was isolated from an 18-month-old child with gastroenteritis admitted to Children's Hospital of Philadelphia in February 1983. The WI61 virus was clearly distinguished by cross-neutralization tests from human rotaviruses of serotypes 1, 2, 3, and 4, human 69M, and representative bovine (NCDV), porcine (OSU), and chicken (Ch2) rotaviruses. Antisera generated in guinea pigs hyperimmunized to WI61 virus displayed a partial cross-reactivity with rotaviruses of human serotypes 1, 2, 3, and 4. By means of studies with reassortant rotaviruses, it was presumptively determined that the WI61 virus cross-reactive antigenic determinants are localized on the vp3 surface polypeptide coded by gene segment 4. The characteristic RNA genome electropherotype of WI61 virus was observed in 5 of 59 cases of infant gastroenteritis detected in 1983 and 1984 but has not been observed in a subsequently at Children's Hospital. Serotype WI61-specific neutralizing antibodies were observed in a majority of sera of normal adults and infants of less than 4 or greater than 12 months of age collected in the Philadelphia area. Median antibody titers to WI61 equaled or exceeded those to rotaviruses of serotype 1 or 3. Each of seven samples of commercial cow's milk exhibited neutralizing antibodies to WI61 virus at a titer greater than or equal to that to serotype 1 or 3 or bovine (strain NCDV) rotavirus. However, WI61 rotavirus did not induce disease or a specific serum-neutralizing antibody response when fed to a caesarean-derived colostrum-deprived newborn calf. WI61 rotavirus caused diarrhea in newborn mice with a 50% diarrhea-inducing dose of 10(7.0) PFU.
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Affiliation(s)
- H F Clark
- Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104
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