Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease
Identifieur interne : 000363 ( Pmc/Checkpoint ); précédent : 000362; suivant : 000364Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease
Auteurs : Xinrong Tao [États-Unis] ; Tania Garron [États-Unis] ; Anurodh Shankar Agrawal [États-Unis] ; Abdullah Algaissi [États-Unis, Arabie saoudite] ; Bi-Hung Peng [États-Unis] ; Maki Wakamiya [États-Unis] ; Teh-Sheng Chan [États-Unis] ; Lu Lu [République populaire de Chine] ; Lanying Du [États-Unis] ; Shibo Jiang [États-Unis] ; Robert B. Couch [États-Unis] ; Chien-Te K. Tseng [États-Unis]Source :
- Journal of Virology [ 0022-538X ] ; 2015.
Abstract
Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID50) and lethal dose (LD50) of virus were estimated to be <1 and 10 TCID50 of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID50/LD50 determinations, and all were fully immune to challenge with 100 LD50 of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD50 of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 105 LD50 of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research.
Url:
DOI: 10.1128/JVI.02009-15
PubMed: 26446606
PubMed Central: 4702581
Affiliations:
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID<sub>50</sub>
) and lethal dose (LD<sub>50</sub>
) of virus were estimated to be <1 and 10 TCID<sub>50</sub>
of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID<sub>50</sub>
/LD<sub>50</sub>
determinations, and all were fully immune to challenge with 100 LD<sub>50</sub>
of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD<sub>50</sub>
of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10<sup>5</sup>
LD<sub>50</sub>
of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research.
</p>
<p><bold>IMPORTANCE</bold>
Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing hCD26/DPP4 viral receptor uniformly succumbed to death within 6 days, making it difficult to evaluate host responses to infection and disease. We further characterized this model by determining both the ID<sub>50</sub>
and the LD<sub>50</sub>
of MERS-CoV in order to establish both an infection model and a lethal model for MERS and followed this by investigating the antibody responses and immunity of the mice that survived MERS-CoV infection. Using the estimated LD<sub>50</sub>
and ID<sub>50</sub>
data, we dissected the kinetics of viral tissue distribution and pathology in mice challenged with 10 LD<sub>50</sub>
of virus and utilized the model for preclinical evaluation of a vaccine and drug for treatment of MERS-CoV infection. This further-characterized transgenic mouse model will be useful for advancing MERS research.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Virol</journal-id>
<journal-id journal-id-type="hwp">jvi</journal-id>
<journal-id journal-id-type="pmc">jvi</journal-id>
<journal-id journal-id-type="publisher-id">JVI</journal-id>
<journal-title-group><journal-title>Journal of Virology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-538X</issn>
<issn pub-type="epub">1098-5514</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
<publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26446606</article-id>
<article-id pub-id-type="pmc">4702581</article-id>
<article-id pub-id-type="publisher-id">02009-15</article-id>
<article-id pub-id-type="doi">10.1128/JVI.02009-15</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject>
</subj-group>
</article-categories>
<title-group><article-title>Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease</article-title>
<alt-title alt-title-type="running-head">Transgenic Mice for MERS-CoV Infection and Disease</alt-title>
<alt-title alt-title-type="short-authors">Tao et al.</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tao</surname>
<given-names>Xinrong</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Garron</surname>
<given-names>Tania</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Agrawal</surname>
<given-names>Anurodh Shankar</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Algaissi</surname>
<given-names>Abdullah</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff8"><sup>h</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peng</surname>
<given-names>Bi-Hung</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wakamiya</surname>
<given-names>Maki</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chan</surname>
<given-names>Teh-Sheng</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lu</surname>
<given-names>Lu</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Du</surname>
<given-names>Lanying</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jiang</surname>
<given-names>Shibo</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Couch</surname>
<given-names>Robert B.</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Tseng</surname>
<given-names>Chien-Te K.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>g</sup>
</xref>
</contrib>
<aff id="aff1"><label>a</label>
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA</aff>
<aff id="aff2"><label>b</label>
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA</aff>
<aff id="aff3"><label>c</label>
Transgenic Mouse Core Facility, Institute for Translational Sciences and Animal Resource Center, University of Texas Medical Branch, Galveston, Texas, USA</aff>
<aff id="aff4"><label>d</label>
Institute of Medical Microbiology, Fudan University, Shanghai, China</aff>
<aff id="aff5"><label>e</label>
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA</aff>
<aff id="aff6"><label>f</label>
Department of Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas, USA</aff>
<aff id="aff7"><label>g</label>
Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch, Galveston, Texas, USA</aff>
<aff id="aff8"><label>h</label>
Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia</aff>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>García-Sastre</surname>
<given-names>A.</given-names>
</name>
<role>Editor</role>
</contrib>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Chien-Te K. Tseng, <email>sktseng@utmb.edu</email>
.</corresp>
<fn fn-type="equal"><p>X.T., T.G., and A.S.A. contributed equally to this article.</p>
</fn>
<fn fn-type="other"><p><bold>Citation</bold>
Tao X, Garron T, Agrawal AS, Algaissi A, Peng B-H, Wakamiya M, Chan T-S, Lu L, Du L, Jiang S, Couch RB, Tseng C-TK. 2016. Characterization and demonstration of the value of a lethal mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 90:57–67. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/JVI.02009-15">10.1128/JVI.02009-15</ext-link>
.</p>
</fn>
</author-notes>
<pub-date pub-type="epreprint"><day>7</day>
<month>10</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><day>1</day>
<month>1</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>17</day>
<month>12</month>
<year>2015</year>
</pub-date>
<volume>90</volume>
<issue>1</issue>
<fpage>57</fpage>
<lpage>67</lpage>
<history><date date-type="received"><day>6</day>
<month>8</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>5</day>
<month>10</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>American Society for Microbiology</copyright-holder>
</permissions>
<self-uri content-type="pdf" xlink:href="zjv00116000057.pdf"></self-uri>
<abstract><title>ABSTRACT</title>
<p>Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID<sub>50</sub>
) and lethal dose (LD<sub>50</sub>
) of virus were estimated to be <1 and 10 TCID<sub>50</sub>
of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID<sub>50</sub>
/LD<sub>50</sub>
determinations, and all were fully immune to challenge with 100 LD<sub>50</sub>
of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD<sub>50</sub>
of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10<sup>5</sup>
LD<sub>50</sub>
of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research.
</p>
<p><bold>IMPORTANCE</bold>
Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing hCD26/DPP4 viral receptor uniformly succumbed to death within 6 days, making it difficult to evaluate host responses to infection and disease. We further characterized this model by determining both the ID<sub>50</sub>
and the LD<sub>50</sub>
of MERS-CoV in order to establish both an infection model and a lethal model for MERS and followed this by investigating the antibody responses and immunity of the mice that survived MERS-CoV infection. Using the estimated LD<sub>50</sub>
and ID<sub>50</sub>
data, we dissected the kinetics of viral tissue distribution and pathology in mice challenged with 10 LD<sub>50</sub>
of virus and utilized the model for preclinical evaluation of a vaccine and drug for treatment of MERS-CoV infection. This further-characterized transgenic mouse model will be useful for advancing MERS research.</p>
</abstract>
<funding-group><award-group id="award1"><funding-source id="gs1">NIH</funding-source>
<award-id rid="gs1">R21AI113206-01</award-id>
<principal-award-recipient>Chien-Te K. Tseng</principal-award-recipient>
</award-group>
<award-group id="award2"><funding-source id="gs2">Galveston National Laboratory</funding-source>
<award-id rid="gs2">5UC7AI094660-05</award-id>
<principal-award-recipient>Chien-Te K. Tseng</principal-award-recipient>
</award-group>
</funding-group>
<counts><fig-count count="5"></fig-count>
<table-count count="2"></table-count>
<equation-count count="0"></equation-count>
<ref-count count="36"></ref-count>
<page-count count="11"></page-count>
<word-count count="8806"></word-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Arabie saoudite</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Texas</li>
<li>État de New York</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Texas"><name sortKey="Tao, Xinrong" sort="Tao, Xinrong" uniqKey="Tao X" first="Xinrong" last="Tao">Xinrong Tao</name>
</region>
<name sortKey="Agrawal, Anurodh Shankar" sort="Agrawal, Anurodh Shankar" uniqKey="Agrawal A" first="Anurodh Shankar" last="Agrawal">Anurodh Shankar Agrawal</name>
<name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name>
<name sortKey="Chan, Teh Sheng" sort="Chan, Teh Sheng" uniqKey="Chan T" first="Teh-Sheng" last="Chan">Teh-Sheng Chan</name>
<name sortKey="Couch, Robert B" sort="Couch, Robert B" uniqKey="Couch R" first="Robert B." last="Couch">Robert B. Couch</name>
<name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name>
<name sortKey="Garron, Tania" sort="Garron, Tania" uniqKey="Garron T" first="Tania" last="Garron">Tania Garron</name>
<name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<name sortKey="Peng, Bi Hung" sort="Peng, Bi Hung" uniqKey="Peng B" first="Bi-Hung" last="Peng">Bi-Hung Peng</name>
<name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name>
<name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name>
<name sortKey="Wakamiya, Maki" sort="Wakamiya, Maki" uniqKey="Wakamiya M" first="Maki" last="Wakamiya">Maki Wakamiya</name>
</country>
<country name="Arabie saoudite"><noRegion><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name>
</noRegion>
</country>
<country name="République populaire de Chine"><noRegion><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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