The Domestic and International Impacts of the 2009-H1N1 Influenza A Pandemic Global Challenges, Global Solutions: Workshop Summary (2010) / Chapter Skim
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A5 In Vitro and In Vivo Characterization of New Swine-Origin H1N1 Influenza Viruses
A5 In Vitro and In Vivo Characterization of New Swine-Origin H1N1 Influenza Viruses
Pages 155-190
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29 ERATO Infection-Induced Host Responses Project, Saitama 332-0012, Japan. 30 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
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In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms.
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. On day 6 after infection, virus titres followed a similar trend and the lungs of CA04-infected mice showed bronchitis and alveolitis with viral antigen, although signs of regeneration were apparent (Supplementary Figure A5-7c)
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. Collec tively, these findings demonstrate that CA04 causes more severe lung lesions in non-human primates than does a contemporary human influenza virus.
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6.7 4.5 6.6 -- -- -- -- -- -- -- -- 2.3 Conjunctiva 3.6 -- -- -- -- -- -- -- -- -- -- -- Cynomolgus macaques were inoculated with 107.4 p.f.u. of virus (6.7 ml)
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R01627 Representative findings are shown to depict the distribution of lesions inuneditable bitmapped the sections (shown image as cross-sections placed next to illustrations of ach lung lobe) , with or withoutwith viral text replaced antigen, as follows: brown, severe lung lesion containing moderate to many viral-antigen-positive cells; pink, mild lung lesions containing a few viral-antigen-positive cells; blue, lung lesions with alveolar wall thickening, with remaining air spaces unaffected.
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Antiviral compounds are the first line of defence against pandemic influenza viruses. Sequence analysis suggests that S-OIVs are resistant to ion channel inhibitors such as amantadine and rimantadine (Novel Swine-Origin Influenza A (H1N1)
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. Three mice per group were killed on days 3 and 6 after infection and the virus titres in lungs were determined by plaque assays in MDCK cells; results are reported as means ± s.d.
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Our findings indicate that S-OIVs are more pathogenic in mammalian models than seasonal H1N1 influenza viruses. In fact, the ability of CA04 to replicate in the lungs of mice, ferrets and non-human primates, and to cause appreciable pathology in this organ, is reminiscent of infections with highly pathogenic H5N1 influenza viruses (Peiris et al., 2004)
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All experiments with S-OIVs were performed in approved enhanced biosafety level 3 (BSL3) containment laboratories.
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was also isolated from a patient with mild symptoms. The following influenza viruses served as controls: A/Kawasaki/UTK-4/09 (H1N1; KUTK-4; passaged twice in MDCK cells)
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The virus titres in various organs were determined by plaque assays in MDCK cells. Growth Kinetics of Virus in Human Airway Epithelial (HAE)
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The virus titres in nasal washes and various organs were determined by plaque assays in MDCK cells. Experimental Infection of Miniature Pigs Two-month-old female specific-pathogen-free miniature pigs (Nippon Institute for Biological Science)
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To assess viral replication in the upper respiratory tract, viral titres were determined in nasal washes collected from virus-inoculated and contact ferrets on day 1 after inoculation or co-housing, respectively, and then every other day (up to 9 days)
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. Three mice per group were killed on days 3 or 6 after infection and the virus titres in lungs were determined by plaque assays in MDCK cells.
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, by Grant-in-Aid for Specially Promoted Research, by a contract research fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology, and by grants-in-aid from the Ministry of Health and by ERATO (Japan Science and Technology Agency)
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et al. Enhanced expression of an a2,6-linked sialic acid on MDCK cells improves isolation of human influenza viruses and evaluation of their sensitivity to a neuraminidase inhibitor.
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et al. Lack of transmission of H5N1avian-human reassortant influenza viruses in a ferret model.
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. The supernatants of infected cells were harvested at the indicated times and virus titres R01627 were determined by plaque assays in MDCK cells.
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were examined with confocal microscopy R01627 uneditable bitmapped image
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Figure A5-5, part 2 R01627 uneditable bitmapped image
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. Body weights were monitored daily.
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. On day 6 pi, accumulation of cell debris in the bronchiolar lumen with peribronchiolitis was observed, but viral antigens were rarely detected in these lesions (f)
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178 IMPACTS OF THE 2009-H1N1 INFLUENZA A PANDEMIC FIGURE A5-8 Pro-inflammatory cytokine/chemokine responses in the lungs of infected mice. The concentrations of various cytokines/chemokines were measured in the lungs of mice by use of a protein array analysis with the Bio-Plex Mouse Cytokine 23-Plex and 9-Plex panels (Bio-Rad laboratories)
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APPENDIX A 179 FIGURE A5-8 continued
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The periodic sharp reduction in body temperatures on days 0, 1, 3, and 7 was caused by anesthesia requiredR01627 for sampling. Monkeys #1-3 and #7-9 were euthanized on day 3.
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Colors: green, severe lung lesions where alveolar spaces were filled with edema fluid, inflammatory cells, or cell debris; brown, severe lung lesions containingFigure moderate A5-10 to many viral antigen-positive cells; pink, mild lung lesions containing a few viral R01627 antigen-positive cells; blue, lung lesions where uneditable severe alveolar wall thickening bitmapped was prominent, image but air spaces were preserved.
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. Considerable amounts of viral antigen were detected in type II pneumocytes (d)
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APPENDIX A 183 FIGURE A5-12 Pro-inflammatory cytokine/chemokine responses in the lungs of infected cynomolgus macaques. The concentrations of various cytokines/chemokines in the lungs of infected cynomolgus macaques on day 3 post-infection were measured by protein array analysis with the MILLIPLEX MAP Non-human Primate Cytokine/Chemokine Panel – Premixed 23-Plex (Millipore, Bedford, MA)
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Colors: green, severe lung lesions where alveolar spaces were filled with edema fluid, inflammatory cells, or cell debris; brown, severe lung lesions containing moderate to many viral antigen-positive cells.
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(c) Viral antigen was mainly detected in uneditable bitmapped image epithelial cells and desquamated cells.
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None of the viruses tested was recovered from the spleens, kidneys, brains, colons, or livers of infected animals. TABLE A5-3 Virus Titres in Respiratory Swabs from Infected Cynomolgus Macaquesa Virus titre (log10 PFU/ml)
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None of the viruses tested was recovered from the spleens, kidneys, brains, intestines, or livers of infected animals.
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. Nasal swabs were collected from inoculated and contact ferrets every other day for virus titration.
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. 10 TABLE A5-7 Virus Titres in Nasal Swabs from Infected Miniature Pigsa Virus titers (log10 PFU/ml)
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(H1N1) Oseltamivir carboxylatea 0.96c 1.6 1313 1.88 Zanamivir 0.32 0.43 0.79 0.36 R-125489b 0.41 0.44 0.34 0.20 aOseltamivircarboxylate is the active form of oseltamivir.
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