The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease
Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains...
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| description | Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose ( |
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Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD₅₀) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human "severe dengue" cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021024</identifier><identifier>PMID: 21731643</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alveoli ; Animals ; Animals, Outbred Strains ; Antibodies ; Antibodies, Monoclonal - immunology ; Antibodies, Viral - immunology ; Antibody-Dependent Enhancement - immunology ; Antigens ; Antigens, Viral - immunology ; Apoptosis ; B cells ; Biology ; Brain ; Cross Reactions - immunology ; Dengue ; Dengue fever ; Dengue hemorrhagic fever ; Dengue Virus - immunology ; Dengue Virus - physiology ; Encephalitis ; Glycoproteins ; Haplotypes ; Health aspects ; Hepatocytes ; House mouse ; Humans ; Hyperplasia ; Immunoblotting ; Immunoglobulin G ; Immunoglobulins ; Infections ; Leukocytes (mononuclear) ; Lungs ; Macrophages ; Megakaryocytes ; Mice ; Microglia ; Microglial cells ; Multiple Organ Failure - immunology ; Multiple Organ Failure - virology ; Mutation ; Nodules ; Organ Specificity - immunology ; Parenchyma ; Pathogenicity ; Pathogens ; Pneumocytes ; Polyclonal antibodies ; Pulp ; Recombination ; Replication ; Respiratory distress syndrome ; Secretion ; Septum ; Steatosis ; Strains (organisms) ; Studies ; Thickening ; Vaccines ; Vector-borne diseases ; Viral diseases ; Viral Nonstructural Proteins - immunology ; Viral Nonstructural Proteins - isolation & purification ; Virion - immunology ; Virions ; Virology ; Virus replication ; Virus Replication - immunology ; Viruses</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e21024-e21024</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Falconar, Martinez. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Falconar, Martinez. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-66c15ac6ff7c4490e24e31ff9cd469500ca90ecfff6861ed61fb25aff31c19263</citedby><cites>FETCH-LOGICAL-c757t-66c15ac6ff7c4490e24e31ff9cd469500ca90ecfff6861ed61fb25aff31c19263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120820/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120820/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21731643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Schneider, Bradley S.</contributor><creatorcontrib>Falconar, Andrew K I</creatorcontrib><creatorcontrib>Martinez, Fernando</creatorcontrib><title>The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD₅₀) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human "severe dengue" cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice.</description><subject>Alveoli</subject><subject>Animals</subject><subject>Animals, Outbred Strains</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Viral - immunology</subject><subject>Antibody-Dependent Enhancement - immunology</subject><subject>Antigens</subject><subject>Antigens, Viral - immunology</subject><subject>Apoptosis</subject><subject>B cells</subject><subject>Biology</subject><subject>Brain</subject><subject>Cross Reactions - immunology</subject><subject>Dengue</subject><subject>Dengue fever</subject><subject>Dengue hemorrhagic fever</subject><subject>Dengue Virus - immunology</subject><subject>Dengue Virus - physiology</subject><subject>Encephalitis</subject><subject>Glycoproteins</subject><subject>Haplotypes</subject><subject>Health aspects</subject><subject>Hepatocytes</subject><subject>House mouse</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Immunoblotting</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulins</subject><subject>Infections</subject><subject>Leukocytes (mononuclear)</subject><subject>Lungs</subject><subject>Macrophages</subject><subject>Megakaryocytes</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglial cells</subject><subject>Multiple Organ Failure - immunology</subject><subject>Multiple Organ Failure - virology</subject><subject>Mutation</subject><subject>Nodules</subject><subject>Organ Specificity - immunology</subject><subject>Parenchyma</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>Pneumocytes</subject><subject>Polyclonal antibodies</subject><subject>Pulp</subject><subject>Recombination</subject><subject>Replication</subject><subject>Respiratory distress syndrome</subject><subject>Secretion</subject><subject>Septum</subject><subject>Steatosis</subject><subject>Strains (organisms)</subject><subject>Studies</subject><subject>Thickening</subject><subject>Vaccines</subject><subject>Vector-borne diseases</subject><subject>Viral diseases</subject><subject>Viral Nonstructural Proteins - immunology</subject><subject>Viral Nonstructural Proteins - isolation & purification</subject><subject>Virion - immunology</subject><subject>Virions</subject><subject>Virology</subject><subject>Virus replication</subject><subject>Virus Replication - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Falconar, Andrew K I</au><au>Martinez, Fernando</au><au>Schneider, Bradley S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-22</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e21024</spage><epage>e21024</epage><pages>e21024-e21024</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Antibody-enhanced replication (AER) of dengue type-2 virus (DENV-2) strains and production of antibody-enhanced disease (AED) was tested in out-bred mice. Polyclonal antibodies (PAbs) generated against the nonstructural-1 (NS1) glycoprotein candidate vaccine of the New Guinea-C (NG-C) or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E) glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD₅₀) of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS), displayed by diffuse alveolar damage (DAD) resulting from i) dramatic interstitial alveolar septa-thickening with mononuclear cells, ii) some hyperplasia of alveolar type-II pneumocytes, iii) copious intra-alveolar protein secretion, iv) some hyaline membrane-covered alveolar walls, and v) DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human "severe dengue" cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines, particularly against DENV strains that contain multiple mutations or genetic recombination within or between their DENV E and NS1 glycoprotein-encoding genes. The model provides potential for assessing DENV strain pathogenicity and anti-DENV therapies in normal mice.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21731643</pmid><doi>10.1371/journal.pone.0021024</doi><tpages>e21024</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_1304913375 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alveoli Animals Animals, Outbred Strains Antibodies Antibodies, Monoclonal - immunology Antibodies, Viral - immunology Antibody-Dependent Enhancement - immunology Antigens Antigens, Viral - immunology Apoptosis B cells Biology Brain Cross Reactions - immunology Dengue Dengue fever Dengue hemorrhagic fever Dengue Virus - immunology Dengue Virus - physiology Encephalitis Glycoproteins Haplotypes Health aspects Hepatocytes House mouse Humans Hyperplasia Immunoblotting Immunoglobulin G Immunoglobulins Infections Leukocytes (mononuclear) Lungs Macrophages Megakaryocytes Mice Microglia Microglial cells Multiple Organ Failure - immunology Multiple Organ Failure - virology Mutation Nodules Organ Specificity - immunology Parenchyma Pathogenicity Pathogens Pneumocytes Polyclonal antibodies Pulp Recombination Replication Respiratory distress syndrome Secretion Septum Steatosis Strains (organisms) Studies Thickening Vaccines Vector-borne diseases Viral diseases Viral Nonstructural Proteins - immunology Viral Nonstructural Proteins - isolation & purification Virion - immunology Virions Virology Virus replication Virus Replication - immunology Viruses |
| title | The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease |
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