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Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody

Identifieur interne : 001106 ( Pmc/Curation ); précédent : 001105; suivant : 001107

Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody

Auteurs : Katherine V. Houser [États-Unis] ; Andrew J. Broadbent [États-Unis] ; Lisa Gretebeck [États-Unis] ; Leatrice Vogel [États-Unis] ; Elaine W. Lamirande [États-Unis] ; Troy Sutton [États-Unis] ; Kevin W. Bock [États-Unis] ; Mahnaz Minai [États-Unis] ; Marlene Orandle [États-Unis] ; Ian N. Moore [États-Unis] ; Kanta Subbarao [États-Unis]

Source :

RBID : PMC:5574614

Abstract

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non-lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to naïve rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV.


Url:
DOI: 10.1371/journal.ppat.1006565
PubMed: 28817732
PubMed Central: 5574614

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Le document en format XML

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<p>The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non-lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to naïve rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV.</p>
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<alt-title alt-title-type="running-head">Enhanced inflammation after MERS reinfection in rabbits</alt-title>
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<name>
<surname>Houser</surname>
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<xref ref-type="aff" rid="aff001">
<sup>1</sup>
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<name>
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<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
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<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Gretebeck</surname>
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<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
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<name>
<surname>Vogel</surname>
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<role content-type="http://credit.casrai.org/">Data curation</role>
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<xref ref-type="aff" rid="aff001">
<sup>1</sup>
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<name>
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<xref ref-type="aff" rid="aff001">
<sup>1</sup>
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<name>
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</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-9454-0937</contrib-id>
<name>
<surname>Bock</surname>
<given-names>Kevin W.</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-3642-8063</contrib-id>
<name>
<surname>Minai</surname>
<given-names>Mahnaz</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Software</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Orandle</surname>
<given-names>Marlene</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
<role content-type="http://credit.casrai.org/">Formal analysis</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Moore</surname>
<given-names>Ian N.</given-names>
</name>
<role content-type="http://credit.casrai.org/">Data curation</role>
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<role content-type="http://credit.casrai.org/">Investigation</role>
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<role content-type="http://credit.casrai.org/">Software</role>
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<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-1713-3056</contrib-id>
<name>
<surname>Subbarao</surname>
<given-names>Kanta</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
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<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="currentaff001">
<sup>¤</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001">
<label>1</label>
<addr-line>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, United States of America</addr-line>
</aff>
<aff id="aff002">
<label>2</label>
<addr-line>Comparative Medicine Branch, Infectious Disease Pathogenesis Section, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, United States of America</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Kuhn</surname>
<given-names>Jens H.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Division of Clinical Research, UNITED STATES</addr-line>
</aff>
<author-notes>
<fn fn-type="COI-statement" id="coi001">
<p>The authors have declared that no competing interests exist</p>
</fn>
<fn fn-type="current-aff" id="currentaff001">
<label>¤</label>
<p>Current address: WHO Collaborating Centre for Reference and Research on Influenza and the University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia</p>
</fn>
<corresp id="cor001">* E-mail:
<email>ksubbarao@niaid.nih.gov</email>
,
<email>Kanta.subbarao@influenzacentre.org</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>17</day>
<month>8</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection">
<month>8</month>
<year>2017</year>
</pub-date>
<volume>13</volume>
<issue>8</issue>
<elocation-id>e1006565</elocation-id>
<history>
<date date-type="received">
<day>17</day>
<month>2</month>
<year>2017</year>
</date>
<date date-type="accepted">
<day>1</day>
<month>8</month>
<year>2017</year>
</date>
</history>
<permissions>
<license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">
<license-p>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the
<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/publicdomain/zero/1.0/">Creative Commons CC0</ext-link>
public domain dedication.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="ppat.1006565.pdf"></self-uri>
<abstract>
<p>The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non-lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to naïve rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV.</p>
</abstract>
<abstract abstract-type="summary">
<title>Author summary</title>
<p>New Zealand white rabbits display an increase in lung inflammation following reinfection with MERS-CoV that is associated with non-neutralizing antibodies and complement proteins. The development of neutralizing antibodies resulted in protection from infection. These findings may have implications for individuals that fail to develop a neutralizing antibody response, or for those whose response wanes over time, upon re-exposure to MERS-CoV.</p>
</abstract>
<funding-group>
<funding-statement>This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Disease, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<fig-count count="9"></fig-count>
<table-count count="1"></table-count>
<page-count count="25"></page-count>
</counts>
<custom-meta-group>
<custom-meta>
<meta-name>PLOS Publication Stage</meta-name>
<meta-value>vor-update-to-uncorrected-proof</meta-value>
</custom-meta>
<custom-meta>
<meta-name>Publication Update</meta-name>
<meta-value>2017-08-29</meta-value>
</custom-meta>
<custom-meta id="data-availability">
<meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes>
<title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files</p>
</notes>
</front>
</pmc>
</record>

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