Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease
Identifieur interne : 001104 ( Main/Exploration ); précédent : 001103; suivant : 001105Characterization 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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<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>
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<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>
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<country name="Arabie saoudite"><noRegion><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name>
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<country name="République populaire de Chine"><noRegion><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
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