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Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor

Identifieur interne : 003B29 ( Main/Exploration ); précédent : 003B28; suivant : 003B30

Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human angiotensin-converting enzyme 2 virus receptor

Auteurs : Chien-Te K. Tseng [États-Unis] ; CHENG HUANG [États-Unis] ; Patrick Newman [États-Unis] ; NAN WANG [États-Unis] ; Krishna Narayanan [États-Unis] ; Douglas M. Watts [États-Unis] ; Shinji Makino [États-Unis] ; Michelle M. Packard [États-Unis] ; Sherif R. Zaki [États-Unis] ; Teh-Sheng Chan [États-Unis] ; Clarence J. Peters [États-Unis]

Source :

RBID : Pascal:07-0181866

Descripteurs français

English descriptors

Abstract

Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg+) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg-) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg+ mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg+ AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice-AC70 in particular-makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.


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<affiliation wicri:level="2">
<inist:fA14 i1="02">
<s1>Department of Microbiology and Immunology Center of Biodefense and Emerging Infectious Disease, University of Texas Medical Branch</s1>
<s2>Galveston, Texas</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName>
<region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2">
<inist:fA14 i1="03">
<s1>Department of Pathology, University of Texas Medical Branch</s1>
<s2>Galveston, Texas</s2>
<s3>USA</s3>
<sZ>3 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName>
<region type="state">Texas</region>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j" type="main">Journal of virology</title>
<title level="j" type="abbreviated">J. virol.</title>
<idno type="ISSN">0022-538X</idno>
<imprint>
<date when="2007">2007</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt>
<title level="j" type="main">Journal of virology</title>
<title level="j" type="abbreviated">J. virol.</title>
<idno type="ISSN">0022-538X</idno>
</seriesStmt>
</fileDesc>
<profileDesc>
<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>Coronavirus</term>
<term>Human</term>
<term>Mouse</term>
<term>Peptidyl-dipeptidase A</term>
<term>Severe acute respiratory syndrome</term>
<term>Transgenic animal</term>
<term>Virology</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr">
<term>Coronavirus</term>
<term>Animal transgénique</term>
<term>Souris</term>
<term>Homme</term>
<term>Peptidyl-dipeptidase A</term>
<term>Virologie</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr">
<term>Animal transgénique</term>
<term>Homme</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg
<sup>+</sup>
) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg
<sup>-</sup>
) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg
<sup>+</sup>
mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg
<sup>+</sup>
AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice-AC70 in particular-makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>États-Unis</li>
</country>
<region>
<li>Géorgie (États-Unis)</li>
<li>Texas</li>
</region>
</list>
<tree>
<country name="États-Unis">
<region name="Texas">
<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>
</region>
<name sortKey="Chan, Teh Sheng" sort="Chan, Teh Sheng" uniqKey="Chan T" first="Teh-Sheng" last="Chan">Teh-Sheng Chan</name>
<name sortKey="Cheng Huang" sort="Cheng Huang" uniqKey="Cheng Huang" last="Cheng Huang">CHENG HUANG</name>
<name sortKey="Makino, Shinji" sort="Makino, Shinji" uniqKey="Makino S" first="Shinji" last="Makino">Shinji Makino</name>
<name sortKey="Makino, Shinji" sort="Makino, Shinji" uniqKey="Makino S" first="Shinji" last="Makino">Shinji Makino</name>
<name sortKey="Nan Wang" sort="Nan Wang" uniqKey="Nan Wang" last="Nan Wang">NAN WANG</name>
<name sortKey="Narayanan, Krishna" sort="Narayanan, Krishna" uniqKey="Narayanan K" first="Krishna" last="Narayanan">Krishna Narayanan</name>
<name sortKey="Newman, Patrick" sort="Newman, Patrick" uniqKey="Newman P" first="Patrick" last="Newman">Patrick Newman</name>
<name sortKey="Packard, Michelle M" sort="Packard, Michelle M" uniqKey="Packard M" first="Michelle M." last="Packard">Michelle M. Packard</name>
<name sortKey="Peters, Clarence J" sort="Peters, Clarence J" uniqKey="Peters C" first="Clarence J." last="Peters">Clarence J. Peters</name>
<name sortKey="Peters, Clarence J" sort="Peters, Clarence J" uniqKey="Peters C" first="Clarence J." last="Peters">Clarence J. Peters</name>
<name sortKey="Peters, Clarence J" sort="Peters, Clarence J" uniqKey="Peters C" first="Clarence J." last="Peters">Clarence J. Peters</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="Watts, Douglas M" sort="Watts, Douglas M" uniqKey="Watts D" first="Douglas M." last="Watts">Douglas M. Watts</name>
<name sortKey="Watts, Douglas M" sort="Watts, Douglas M" uniqKey="Watts D" first="Douglas M." last="Watts">Douglas M. Watts</name>
<name sortKey="Zaki, Sherif R" sort="Zaki, Sherif R" uniqKey="Zaki S" first="Sherif R." last="Zaki">Sherif R. Zaki</name>
</country>
</tree>
</affiliations>
</record>

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