PandemieGrippaleV1, Main, Curation, bibRecord, 002041

Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque

Identifieur interne : 002041 ( Main/Curation ); précédent : 002040; suivant : 002042

Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque

Auteurs : Kyoko Shinya [Japon] ; YUWEI GAO [République populaire de Chine] ; Cristian Cilloniz [États-Unis] ; Yasuhiro Suzuki [Japon] ; Masahiro Fujie [Japon] ; GUOHUA DENG [République populaire de Chine] ; QIYUN ZHU [République populaire de Chine] ; SHUFANG FAN [République populaire de Chine] ; Akiko Makino [Japon] ; Yukiko Muramoto [Japon] ; Satoshi Fukuyama [Japon] ; Daisuke Tamura [Japon] ; Takeshi Noda [Japon] ; Amie J. Eisfeld [États-Unis] ; Michael G. Katze [États-Unis] ; HUALAN CHEN [République populaire de Chine] ; Yoshihiro Kawaoka [Japon, États-Unis]

Source :

Journal of virology [ 0022-538X ] ; 2012.

RBID : Pascal:12-0227858

Descripteurs français

Pascal (Inist)
- Influenzavirus aviaire, Virus grippal A, Macaca mulatta, Pneumonie virale.

English descriptors

KwdEn :
- Avian influenzavirus, Influenza A virus, Macaca mulatta, Viral pneumonia.

Abstract

Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease.

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Le document en format XML

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<author><name sortKey="Muramoto, Yukiko" sort="Muramoto, Yukiko" uniqKey="Muramoto Y" first="Yukiko" last="Muramoto">Yukiko Muramoto</name>
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<s2>Minato-ku, Tokyo</s2>
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<author><name sortKey="Fukuyama, Satoshi" sort="Fukuyama, Satoshi" uniqKey="Fukuyama S" first="Satoshi" last="Fukuyama">Satoshi Fukuyama</name>
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<author><name sortKey="Tamura, Daisuke" sort="Tamura, Daisuke" uniqKey="Tamura D" first="Daisuke" last="Tamura">Daisuke Tamura</name>
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<author><name sortKey="Noda, Takeshi" sort="Noda, Takeshi" uniqKey="Noda T" first="Takeshi" last="Noda">Takeshi Noda</name>
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</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
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<author><name sortKey="Eisfeld, Amie J" sort="Eisfeld, Amie J" uniqKey="Eisfeld A" first="Amie J." last="Eisfeld">Amie J. Eisfeld</name>
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<author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
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<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
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<author><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Zoonosis, Department of Microbiology and Infectious Disease, Graduate School of Medicine, Kobe University, Kusunoki-cho, Chuo-ku</s1>
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<region type="province">Région de Kantō</region>
</placeName>
<orgName type="university" n="3">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>10 aut.</sZ>
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<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency</s1>
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<s3>JPN</s3>
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<wicri:noRegion>Saitama</wicri:noRegion>
<placeName><settlement type="city">Tokyo</settlement>
<region type="province">Région de Kantō</region>
</placeName>
<orgName type="university" n="3">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="07"><s1>International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>13 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</affiliation>
<affiliation wicri:level="2"><inist:fA14 i1="08"><s1>Influenza Research Institute, Department of Pathological Sciences, University of Wisconsin-Madison</s1>
<s2>Madison, Wisconsin</s2>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Wisconsin</region>
</placeName>
<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque</title>
<author><name sortKey="Shinya, Kyoko" sort="Shinya, Kyoko" uniqKey="Shinya K" first="Kyoko" last="Shinya">Kyoko Shinya</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Zoonosis, Department of Microbiology and Infectious Disease, Graduate School of Medicine, Kobe University, Kusunoki-cho, Chuo-ku</s1>
<s2>Kobe, Hyogo</s2>
<s3>JPN</s3>
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<country>Japon</country>
<wicri:noRegion>Kobe, Hyogo</wicri:noRegion>
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<author><name sortKey="Yuwei Gao" sort="Yuwei Gao" uniqKey="Yuwei Gao" last="Yuwei Gao">YUWEI GAO</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
<s2>Harbin</s2>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
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<author><name sortKey="Cilloniz, Cristian" sort="Cilloniz, Cristian" uniqKey="Cilloniz C" first="Cristian" last="Cilloniz">Cristian Cilloniz</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, School of Medicine, University of Washington</s1>
<s2>Seattle, Washington</s2>
<s3>USA</s3>
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<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Suzuki, Yasuhiro" sort="Suzuki, Yasuhiro" uniqKey="Suzuki Y" first="Yasuhiro" last="Suzuki">Yasuhiro Suzuki</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Complex Systems Science, Graduate School of Information Science, Nagoya University, Furo-cho</s1>
<s2>Chikusa-ku, Nagoya</s2>
<s3>JPN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
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<country>Japon</country>
<wicri:noRegion>Chikusa-ku, Nagoya</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Fujie, Masahiro" sort="Fujie, Masahiro" uniqKey="Fujie M" first="Masahiro" last="Fujie">Masahiro Fujie</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Complex Systems Science, Graduate School of Information Science, Nagoya University, Furo-cho</s1>
<s2>Chikusa-ku, Nagoya</s2>
<s3>JPN</s3>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<wicri:noRegion>Chikusa-ku, Nagoya</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Guohua Deng" sort="Guohua Deng" uniqKey="Guohua Deng" last="Guohua Deng">GUOHUA DENG</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
<s2>Harbin</s2>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
<wicri:noRegion>Harbin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Qiyun Zhu" sort="Qiyun Zhu" uniqKey="Qiyun Zhu" last="Qiyun Zhu">QIYUN ZHU</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
<s2>Harbin</s2>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
<wicri:noRegion>Harbin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Shufang Fan" sort="Shufang Fan" uniqKey="Shufang Fan" last="Shufang Fan">SHUFANG FAN</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
<s2>Harbin</s2>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
<wicri:noRegion>Harbin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Makino, Akiko" sort="Makino, Akiko" uniqKey="Makino A" first="Akiko" last="Makino">Akiko Makino</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Zoonosis, Department of Microbiology and Infectious Disease, Graduate School of Medicine, Kobe University, Kusunoki-cho, Chuo-ku</s1>
<s2>Kobe, Hyogo</s2>
<s3>JPN</s3>
<sZ>1 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<wicri:noRegion>Kobe, Hyogo</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Muramoto, Yukiko" sort="Muramoto, Yukiko" uniqKey="Muramoto Y" first="Yukiko" last="Muramoto">Yukiko Muramoto</name>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
</author>
<author><name sortKey="Fukuyama, Satoshi" sort="Fukuyama, Satoshi" uniqKey="Fukuyama S" first="Satoshi" last="Fukuyama">Satoshi Fukuyama</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency</s1>
<s2>Saitama</s2>
<s3>JPN</s3>
<sZ>11 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<wicri:noRegion>Saitama</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Tamura, Daisuke" sort="Tamura, Daisuke" uniqKey="Tamura D" first="Daisuke" last="Tamura">Daisuke Tamura</name>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
</author>
<author><name sortKey="Noda, Takeshi" sort="Noda, Takeshi" uniqKey="Noda T" first="Takeshi" last="Noda">Takeshi Noda</name>
<affiliation wicri:level="4"><inist:fA14 i1="07"><s1>International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>13 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
</affiliation>
</author>
<author><name sortKey="Eisfeld, Amie J" sort="Eisfeld, Amie J" uniqKey="Eisfeld A" first="Amie J." last="Eisfeld">Amie J. Eisfeld</name>
<affiliation wicri:level="2"><inist:fA14 i1="08"><s1>Influenza Research Institute, Department of Pathological Sciences, University of Wisconsin-Madison</s1>
<s2>Madison, Wisconsin</s2>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Wisconsin</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, School of Medicine, University of Washington</s1>
<s2>Seattle, Washington</s2>
<s3>USA</s3>
<sZ>3 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Hualan Chen" sort="Hualan Chen" uniqKey="Hualan Chen" last="Hualan Chen">HUALAN CHEN</name>
<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Animal Influenza Laboratory of the Ministry of Agriculture and State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences</s1>
<s2>Harbin</s2>
<s3>CHN</s3>
<sZ>2 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
<country>République populaire de Chine</country>
<wicri:noRegion>Harbin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kawaoka, Yoshihiro" sort="Kawaoka, Yoshihiro" uniqKey="Kawaoka Y" first="Yoshihiro" last="Kawaoka">Yoshihiro Kawaoka</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Zoonosis, Department of Microbiology and Infectious Disease, Graduate School of Medicine, Kobe University, Kusunoki-cho, Chuo-ku</s1>
<s2>Kobe, Hyogo</s2>
<s3>JPN</s3>
<sZ>1 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<wicri:noRegion>Kobe, Hyogo</wicri:noRegion>
<placeName><settlement type="city">Tokyo</settlement>
<region type="province">Région de Kantō</region>
</placeName>
<orgName type="university" n="3">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</affiliation>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency</s1>
<s2>Saitama</s2>
<s3>JPN</s3>
<sZ>11 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<wicri:noRegion>Saitama</wicri:noRegion>
<placeName><settlement type="city">Tokyo</settlement>
<region type="province">Région de Kantō</region>
</placeName>
<orgName type="university" n="3">Université de Tokyo</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="07"><s1>International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Shirokanedai</s1>
<s2>Minato-ku, Tokyo</s2>
<s3>JPN</s3>
<sZ>13 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>Japon</country>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
<orgName type="university">Université de Tokyo</orgName>
<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</affiliation>
<affiliation wicri:level="2"><inist:fA14 i1="08"><s1>Influenza Research Institute, Department of Pathological Sciences, University of Wisconsin-Madison</s1>
<s2>Madison, Wisconsin</s2>
<s3>USA</s3>
<sZ>14 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Wisconsin</region>
</placeName>
<placeName><settlement type="city">Madison (Wisconsin)</settlement>
<region type="state">Wisconsin</region>
</placeName>
<orgName type="university" n="3">Université du Wisconsin à Madison</orgName>
</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="2012">2012</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>Avian influenzavirus</term>
<term>Influenza A virus</term>
<term>Macaca mulatta</term>
<term>Viral pneumonia</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Influenzavirus aviaire</term>
<term>Virus grippal A</term>
<term>Macaca mulatta</term>
<term>Pneumonie virale</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease.</div>
</front>
</TEI>
</record>

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Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque

Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque

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