Virulence attenuation of Dengue virus due to augmented glycosaminoglycan-binding affinity and restriction in extraneural dissemination
1 John Curtin School of Medical Research, Division of Immunology and Genetics, Australian National University, PO Box 334, Canberra, ACT 2600, Australia 2 Department of Microbiology, Monash University, Clayton, VIC, Australia 3 Department of Cellular and Molecular Medicine, University of Bristol, Br...
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| Veröffentlicht in: | Journal of general virology 2006-10, Vol.87 (10), p.2791-2801 |
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| creator | Lee, Eva Wright, Peter J Davidson, Andrew Lobigs, Mario |
| description | 1 John Curtin School of Medical Research, Division of Immunology and Genetics, Australian National University, PO Box 334, Canberra, ACT 2600, Australia
2 Department of Microbiology, Monash University, Clayton, VIC, Australia
3 Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
Correspondence Eva Lee Eva.Lee{at}anu.edu.au
To gain insight into the role of cell surface glycosaminoglycans (GAG) in dengue virus (DEN) cell tropism and virulence, DEN-2 mouse brain-adapted vaccine candidate, neurovirulent prototype strain (NGC) and low-passage strain, PUO-218, were passaged in BHK-21 and SW13 cells to isolate variants with high affinity for GAG. Sequence comparisons of parent and passage variants revealed five GAG-binding determinants, which all cluster in a surface-exposed region in domain II of the three-dimensional structure of the DEN envelope protein. Using an infectious cDNA clone of NGC and an NGC/PUO-218 prME chimeric clone, it was demonstrated that the GAG-binding determinants augment the specific infectivity for BHK-21 and/or SW13 cells by 10- to 170-fold and in some cases marginally reduce that for Vero cells. This altered cell tropism was due to a greater dependence of the variants on cell surface GAG for attachment/entry, given their increased susceptibility to heparin inhibition. The effect of the GAG-binding determinants on virulence was examined in mice deficient in alpha/beta/gamma interferon responses. High GAG affinity strongly correlated with low neuroinvasiveness due to rapid virus clearance from the blood. It was speculated that this mechanism accounts for the attenuation in primates of some DEN vaccine candidates. Interestingly, the GAG-binding variants did not display marked attenuation of neurovirulence and the opposing effect of enhanced neurovirulence was associated with one determinant (Lys 126 ) already present in mouse brain-adapted NGC. This discrepancy of attenuated neuroinvasiveness and augmented neurovirulence may be reconciled by the existence of different mechanisms of virus dissemination in the brain and in extraneural tissues.
Published online ahead of print on 20 June 2006 as DOI 10.1099/vir.0.82164-0. |
| doi_str_mv | 10.1099/vir.0.82164-0 |
| format | Article |
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2 Department of Microbiology, Monash University, Clayton, VIC, Australia
3 Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
Correspondence Eva Lee Eva.Lee{at}anu.edu.au
To gain insight into the role of cell surface glycosaminoglycans (GAG) in dengue virus (DEN) cell tropism and virulence, DEN-2 mouse brain-adapted vaccine candidate, neurovirulent prototype strain (NGC) and low-passage strain, PUO-218, were passaged in BHK-21 and SW13 cells to isolate variants with high affinity for GAG. Sequence comparisons of parent and passage variants revealed five GAG-binding determinants, which all cluster in a surface-exposed region in domain II of the three-dimensional structure of the DEN envelope protein. Using an infectious cDNA clone of NGC and an NGC/PUO-218 prME chimeric clone, it was demonstrated that the GAG-binding determinants augment the specific infectivity for BHK-21 and/or SW13 cells by 10- to 170-fold and in some cases marginally reduce that for Vero cells. This altered cell tropism was due to a greater dependence of the variants on cell surface GAG for attachment/entry, given their increased susceptibility to heparin inhibition. The effect of the GAG-binding determinants on virulence was examined in mice deficient in alpha/beta/gamma interferon responses. High GAG affinity strongly correlated with low neuroinvasiveness due to rapid virus clearance from the blood. It was speculated that this mechanism accounts for the attenuation in primates of some DEN vaccine candidates. Interestingly, the GAG-binding variants did not display marked attenuation of neurovirulence and the opposing effect of enhanced neurovirulence was associated with one determinant (Lys 126 ) already present in mouse brain-adapted NGC. This discrepancy of attenuated neuroinvasiveness and augmented neurovirulence may be reconciled by the existence of different mechanisms of virus dissemination in the brain and in extraneural tissues.
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2 Department of Microbiology, Monash University, Clayton, VIC, Australia
3 Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
Correspondence Eva Lee Eva.Lee{at}anu.edu.au
To gain insight into the role of cell surface glycosaminoglycans (GAG) in dengue virus (DEN) cell tropism and virulence, DEN-2 mouse brain-adapted vaccine candidate, neurovirulent prototype strain (NGC) and low-passage strain, PUO-218, were passaged in BHK-21 and SW13 cells to isolate variants with high affinity for GAG. Sequence comparisons of parent and passage variants revealed five GAG-binding determinants, which all cluster in a surface-exposed region in domain II of the three-dimensional structure of the DEN envelope protein. Using an infectious cDNA clone of NGC and an NGC/PUO-218 prME chimeric clone, it was demonstrated that the GAG-binding determinants augment the specific infectivity for BHK-21 and/or SW13 cells by 10- to 170-fold and in some cases marginally reduce that for Vero cells. This altered cell tropism was due to a greater dependence of the variants on cell surface GAG for attachment/entry, given their increased susceptibility to heparin inhibition. The effect of the GAG-binding determinants on virulence was examined in mice deficient in alpha/beta/gamma interferon responses. High GAG affinity strongly correlated with low neuroinvasiveness due to rapid virus clearance from the blood. It was speculated that this mechanism accounts for the attenuation in primates of some DEN vaccine candidates. Interestingly, the GAG-binding variants did not display marked attenuation of neurovirulence and the opposing effect of enhanced neurovirulence was associated with one determinant (Lys 126 ) already present in mouse brain-adapted NGC. This discrepancy of attenuated neuroinvasiveness and augmented neurovirulence may be reconciled by the existence of different mechanisms of virus dissemination in the brain and in extraneural tissues.
Published online ahead of print on 20 June 2006 as DOI 10.1099/vir.0.82164-0.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Chlorocebus aethiops</subject><subject>Cricetinae</subject><subject>Dengue virus</subject><subject>Dengue Virus - genetics</subject><subject>Dengue Virus - metabolism</subject><subject>Dengue Virus - pathogenicity</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycosaminoglycans - metabolism</subject><subject>Heparin - metabolism</subject><subject>Humans</subject><subject>Interferon gamma Receptor</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microbiology</subject><subject>Miscellaneous</subject><subject>Movement</subject><subject>Mutation</subject><subject>Primates</subject><subject>Protein Binding</subject><subject>Receptor, Interferon alpha-beta</subject><subject>Receptors, Interferon - genetics</subject><subject>Vero Cells</subject><subject>Virology</subject><subject>Virulence</subject><issn>0022-1317</issn><issn>1465-2099</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EotvCkSvyBSQOWfyROPYRFShIlbgAV8uxJ6lR4hR_APsH-N04uyv1yGlGmmfeeTUvQi8o2VOi1NtfPu7JXjIq2oY8Qjvaiq5hdfIY7QhhrKGc9hfoMqUfhNC27fqn6IIKJXjP-x36-93HMkOwgE3OEIrJfg14HfF7CFMBXPVLwq52ecWmTAuEDA5P88GuySw-rFtrQjP44HyYsBlHH3w-YBMcjpBy9Pao6QOGPzmaACWaGTufEtT948Fn6Mlo5gTPz_UKffv44ev1p-b2y83n63e3jW0VzY2gSnLpzCCVMa0QzlkqyDAqA4IxO3JhgVPRSdV1kvZyEIo5KygByUzrOL9Cr0-693H9Wao5vfhkYZ6rq7UkLaRsOZHyvyAjnEvGN8XmBNq4phRh1PfRLyYeNCV6S0jXD2qijwlpUvmXZ-EyLOAe6HMkFXh1BkyyZh7rw6xPD5ykTIm-q9ybE3fnp7vfPoKeICy-2hj8uh2V_WaB9Yryf2WGq0I</recordid><startdate>20061001</startdate><enddate>20061001</enddate><creator>Lee, Eva</creator><creator>Wright, Peter J</creator><creator>Davidson, Andrew</creator><creator>Lobigs, Mario</creator><general>Soc General Microbiol</general><general>Society for General Microbiology</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>C1K</scope><scope>F1W</scope><scope>H94</scope><scope>H97</scope><scope>L.G</scope><scope>7X8</scope></search><sort><creationdate>20061001</creationdate><title>Virulence attenuation of Dengue virus due to augmented glycosaminoglycan-binding affinity and restriction in extraneural dissemination</title><author>Lee, Eva ; Wright, Peter J ; Davidson, Andrew ; Lobigs, Mario</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-619838dab89aa466ddc160bf9ae622cf36ce316589558178b692dc610e82a4d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Chlorocebus aethiops</topic><topic>Cricetinae</topic><topic>Dengue virus</topic><topic>Dengue Virus - genetics</topic><topic>Dengue Virus - metabolism</topic><topic>Dengue Virus - pathogenicity</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glycosaminoglycans - metabolism</topic><topic>Heparin - metabolism</topic><topic>Humans</topic><topic>Interferon gamma Receptor</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microbiology</topic><topic>Miscellaneous</topic><topic>Movement</topic><topic>Mutation</topic><topic>Primates</topic><topic>Protein Binding</topic><topic>Receptor, Interferon alpha-beta</topic><topic>Receptors, Interferon - genetics</topic><topic>Vero Cells</topic><topic>Virology</topic><topic>Virulence</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Eva</creatorcontrib><creatorcontrib>Wright, Peter J</creatorcontrib><creatorcontrib>Davidson, Andrew</creatorcontrib><creatorcontrib>Lobigs, Mario</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of general virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Eva</au><au>Wright, Peter J</au><au>Davidson, Andrew</au><au>Lobigs, Mario</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Virulence attenuation of Dengue virus due to augmented glycosaminoglycan-binding affinity and restriction in extraneural dissemination</atitle><jtitle>Journal of general virology</jtitle><addtitle>J Gen Virol</addtitle><date>2006-10-01</date><risdate>2006</risdate><volume>87</volume><issue>10</issue><spage>2791</spage><epage>2801</epage><pages>2791-2801</pages><issn>0022-1317</issn><eissn>1465-2099</eissn><coden>JGVIAY</coden><abstract>1 John Curtin School of Medical Research, Division of Immunology and Genetics, Australian National University, PO Box 334, Canberra, ACT 2600, Australia
2 Department of Microbiology, Monash University, Clayton, VIC, Australia
3 Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
Correspondence Eva Lee Eva.Lee{at}anu.edu.au
To gain insight into the role of cell surface glycosaminoglycans (GAG) in dengue virus (DEN) cell tropism and virulence, DEN-2 mouse brain-adapted vaccine candidate, neurovirulent prototype strain (NGC) and low-passage strain, PUO-218, were passaged in BHK-21 and SW13 cells to isolate variants with high affinity for GAG. Sequence comparisons of parent and passage variants revealed five GAG-binding determinants, which all cluster in a surface-exposed region in domain II of the three-dimensional structure of the DEN envelope protein. Using an infectious cDNA clone of NGC and an NGC/PUO-218 prME chimeric clone, it was demonstrated that the GAG-binding determinants augment the specific infectivity for BHK-21 and/or SW13 cells by 10- to 170-fold and in some cases marginally reduce that for Vero cells. This altered cell tropism was due to a greater dependence of the variants on cell surface GAG for attachment/entry, given their increased susceptibility to heparin inhibition. The effect of the GAG-binding determinants on virulence was examined in mice deficient in alpha/beta/gamma interferon responses. High GAG affinity strongly correlated with low neuroinvasiveness due to rapid virus clearance from the blood. It was speculated that this mechanism accounts for the attenuation in primates of some DEN vaccine candidates. Interestingly, the GAG-binding variants did not display marked attenuation of neurovirulence and the opposing effect of enhanced neurovirulence was associated with one determinant (Lys 126 ) already present in mouse brain-adapted NGC. This discrepancy of attenuated neuroinvasiveness and augmented neurovirulence may be reconciled by the existence of different mechanisms of virus dissemination in the brain and in extraneural tissues.
Published online ahead of print on 20 June 2006 as DOI 10.1099/vir.0.82164-0.</abstract><cop>Reading</cop><pub>Soc General Microbiol</pub><pmid>16963737</pmid><doi>10.1099/vir.0.82164-0</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Cell Line Chlorocebus aethiops Cricetinae Dengue virus Dengue Virus - genetics Dengue Virus - metabolism Dengue Virus - pathogenicity Fundamental and applied biological sciences. Psychology Glycosaminoglycans - metabolism Heparin - metabolism Humans Interferon gamma Receptor Mice Mice, Knockout Microbiology Miscellaneous Movement Mutation Primates Protein Binding Receptor, Interferon alpha-beta Receptors, Interferon - genetics Vero Cells Virology Virulence |
| title | Virulence attenuation of Dengue virus due to augmented glycosaminoglycan-binding affinity and restriction in extraneural dissemination |
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