MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV
Identifieur interne : 003069 ( Main/Exploration ); précédent : 003068; suivant : 003070MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV
Auteurs : Timothy Sheahan [États-Unis] ; Thomas E. Morrison [États-Unis] ; William Funkhouser [États-Unis] ; Satoshi Uematsu [Japon] ; Shizou Akira [Japon] ; Ralph S. Baric [États-Unis] ; Mark T. Heise [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2008.
Descripteurs français
- KwdFr :
- Animaux, Charge virale, Culture virale, Cytokines (immunologie), Cytokines (métabolisme), Expression des gènes (immunologie), Facteur de différenciation myéloïde-88 (génétique), Facteur de différenciation myéloïde-88 (métabolisme), Immunité innée, Macrophages (immunologie), Modèles animaux de maladie humaine, Monocytes (immunologie), Poumon (anatomopathologie), Poumon (immunologie), Poumon (virologie), Récepteurs CCR (immunologie), Récepteurs CCR (métabolisme), Réplication virale, Souris, Souris de lignée BALB C, Souris knockout, Statistique non paramétrique, Syndrome respiratoire aigu sévère (immunologie), Syndrome respiratoire aigu sévère (mortalité), Syndrome respiratoire aigu sévère (virologie), Transduction du signal, Virus du SRAS (génétique), Virus du SRAS (pathogénicité), Virus du SRAS (physiologie).
- MESH :
- anatomopathologie : Poumon.
- génétique : Facteur de différenciation myéloïde-88, Virus du SRAS.
- immunologie : Cytokines, Expression des gènes, Macrophages, Monocytes, Poumon, Récepteurs CCR, Syndrome respiratoire aigu sévère.
- mortalité : Syndrome respiratoire aigu sévère.
- métabolisme : Cytokines, Facteur de différenciation myéloïde-88, Récepteurs CCR.
- pathogénicité : Virus du SRAS.
- physiologie : Virus du SRAS.
- virologie : Poumon, Syndrome respiratoire aigu sévère.
- Animaux, Charge virale, Culture virale, Immunité innée, Modèles animaux de maladie humaine, Réplication virale, Souris, Souris de lignée BALB C, Souris knockout, Statistique non paramétrique, Transduction du signal.
English descriptors
- KwdEn :
- Animals, Cytokines (immunology), Cytokines (metabolism), Disease Models, Animal, Gene Expression (immunology), Immunity, Innate, Lung (immunology), Lung (pathology), Lung (virology), Macrophages (immunology), Mice, Mice, Inbred BALB C, Mice, Knockout, Monocytes (immunology), Myeloid Differentiation Factor 88 (genetics), Myeloid Differentiation Factor 88 (metabolism), Receptors, CCR (immunology), Receptors, CCR (metabolism), SARS Virus (genetics), SARS Virus (pathogenicity), SARS Virus (physiology), Severe Acute Respiratory Syndrome (immunology), Severe Acute Respiratory Syndrome (mortality), Severe Acute Respiratory Syndrome (virology), Signal Transduction, Statistics, Nonparametric, Viral Load, Virus Cultivation, Virus Replication.
- MESH :
- chemical , genetics : Myeloid Differentiation Factor 88.
- chemical , immunology : Cytokines, Receptors, CCR.
- chemical , metabolism : Cytokines, Myeloid Differentiation Factor 88, Receptors, CCR.
- genetics : SARS Virus.
- immunology : Gene Expression, Lung, Macrophages, Monocytes, Severe Acute Respiratory Syndrome.
- mortality : Severe Acute Respiratory Syndrome.
- pathogenicity : SARS Virus.
- pathology : Lung.
- physiology : SARS Virus.
- virology : Lung, Severe Acute Respiratory Syndrome.
- Animals, Disease Models, Animal, Immunity, Innate, Mice, Mice, Inbred BALB C, Mice, Knockout, Signal Transduction, Statistics, Nonparametric, Viral Load, Virus Cultivation, Virus Replication.
Abstract
A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88−/−), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88−/− mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88−/− mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88−/−mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.
Url:
DOI: 10.1371/journal.ppat.1000240
PubMed: 19079579
PubMed Central: 2587915
Affiliations:
- Japon, États-Unis
- Caroline du Nord
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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Le document en format XML
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North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Morrison, Thomas E" sort="Morrison, Thomas E" uniqKey="Morrison T" first="Thomas E." last="Morrison">Thomas E. Morrison</name><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff4"><addr-line>Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Funkhouser, William" sort="Funkhouser, William" uniqKey="Funkhouser W" first="William" last="Funkhouser">William Funkhouser</name><affiliation wicri:level="2"><nlm:aff id="aff5"><addr-line>Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Uematsu, Satoshi" sort="Uematsu, Satoshi" uniqKey="Uematsu S" first="Satoshi" last="Uematsu">Satoshi Uematsu</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Akira, Shizou" sort="Akira, Shizou" uniqKey="Akira S" first="Shizou" last="Akira">Shizou Akira</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, Suita, Osaka, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name><affiliation wicri:level="4"><nlm:aff id="aff1"><addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina at Chapel Hill, Chapel 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Respiratory Syndrome (mortality)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Signal Transduction</term><term>Statistics, Nonparametric</term><term>Viral Load</term><term>Virus Cultivation</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Charge virale</term><term>Culture virale</term><term>Cytokines (immunologie)</term><term>Cytokines (métabolisme)</term><term>Expression des gènes (immunologie)</term><term>Facteur de différenciation myéloïde-88 (génétique)</term><term>Facteur de différenciation myéloïde-88 (métabolisme)</term><term>Immunité innée</term><term>Macrophages (immunologie)</term><term>Modèles animaux de maladie humaine</term><term>Monocytes (immunologie)</term><term>Poumon (anatomopathologie)</term><term>Poumon (immunologie)</term><term>Poumon (virologie)</term><term>Récepteurs CCR (immunologie)</term><term>Récepteurs CCR (métabolisme)</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris knockout</term><term>Statistique non paramétrique</term><term>Syndrome respiratoire aigu sévère (immunologie)</term><term>Syndrome respiratoire aigu sévère (mortalité)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Transduction du signal</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (pathogénicité)</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Myeloid Differentiation Factor 88</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Cytokines</term><term>Receptors, CCR</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cytokines</term><term>Myeloid Differentiation Factor 88</term><term>Receptors, CCR</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur de différenciation myéloïde-88</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Cytokines</term><term>Expression des gènes</term><term>Macrophages</term><term>Monocytes</term><term>Poumon</term><term>Récepteurs CCR</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Gene Expression</term><term>Lung</term><term>Macrophages</term><term>Monocytes</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="mortality" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="mortalité" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cytokines</term><term>Facteur de différenciation myéloïde-88</term><term>Récepteurs CCR</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Poumon</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Lung</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Immunity, Innate</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Knockout</term><term>Signal Transduction</term><term>Statistics, Nonparametric</term><term>Viral Load</term><term>Virus Cultivation</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Charge virale</term><term>Culture virale</term><term>Immunité innée</term><term>Modèles animaux de maladie humaine</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris knockout</term><term>Statistique non paramétrique</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88<sup>−/−</sup>), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88<sup>−/−</sup> mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88<sup>−/−</sup> mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88<sup>−/−</sup>mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rota, Pa" uniqKey="Rota P">PA Rota</name></author><author><name sortKey="Oberste, Ms" uniqKey="Oberste M">MS Oberste</name></author><author><name sortKey="Monroe, Ss" uniqKey="Monroe S">SS Monroe</name></author><author><name sortKey="Nix, Wa" uniqKey="Nix W">WA Nix</name></author><author><name sortKey="Campagnoli, R" uniqKey="Campagnoli R">R Campagnoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ksiazek, Tg" uniqKey="Ksiazek T">TG Ksiazek</name></author><author><name sortKey="Erdman, D" uniqKey="Erdman D">D Erdman</name></author><author><name sortKey="Goldsmith, Cs" uniqKey="Goldsmith C">CS Goldsmith</name></author><author><name sortKey="Zaki, Sr" uniqKey="Zaki S">SR 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Zhan</name></author><author><name sortKey="Wu, L" uniqKey="Wu L">L Wu</name></author><author><name sortKey="Yu, X" uniqKey="Yu X">X Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheung, Cy" uniqKey="Cheung C">CY Cheung</name></author><author><name sortKey="Poon, Ll" uniqKey="Poon L">LL Poon</name></author><author><name sortKey="Ng, Ih" uniqKey="Ng I">IH Ng</name></author><author><name sortKey="Luk, W" uniqKey="Luk W">W Luk</name></author><author><name sortKey="Sia, Sf" uniqKey="Sia S">SF Sia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Charo, If" uniqKey="Charo I">IF Charo</name></author><author><name sortKey="Ransohoff, Rm" uniqKey="Ransohoff R">RM Ransohoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Glass, Wg" uniqKey="Glass W">WG Glass</name></author><author><name sortKey="Liu, Mt" uniqKey="Liu M">MT Liu</name></author><author><name sortKey="Kuziel, Wa" uniqKey="Kuziel W">WA Kuziel</name></author><author><name sortKey="Lane, Te" uniqKey="Lane T">TE Lane</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hickey, Mj" uniqKey="Hickey M">MJ Hickey</name></author><author><name sortKey="Held, Ks" uniqKey="Held K">KS Held</name></author><author><name sortKey="Baum, E" uniqKey="Baum E">E Baum</name></author><author><name sortKey="Gao, Jl" uniqKey="Gao J">JL Gao</name></author><author><name sortKey="Murphy, Pm" uniqKey="Murphy P">PM Murphy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Held, Ks" uniqKey="Held K">KS Held</name></author><author><name sortKey="Chen, Bp" uniqKey="Chen B">BP Chen</name></author><author><name sortKey="Kuziel, Wa" uniqKey="Kuziel W">WA Kuziel</name></author><author><name sortKey="Rollins, Bj" uniqKey="Rollins B">BJ Rollins</name></author><author><name sortKey="Lane, Te" uniqKey="Lane T">TE Lane</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Glass, Wg" uniqKey="Glass W">WG Glass</name></author><author><name sortKey="Lim, Jk" uniqKey="Lim J">JK Lim</name></author><author><name sortKey="Cholera, R" uniqKey="Cholera R">R Cholera</name></author><author><name sortKey="Pletnev, Ag" uniqKey="Pletnev A">AG Pletnev</name></author><author><name sortKey="Gao, Jl" uniqKey="Gao J">JL Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yount, B" uniqKey="Yount B">B Yount</name></author><author><name sortKey="Curtis, Km" uniqKey="Curtis K">KM Curtis</name></author><author><name sortKey="Fritz, Ea" uniqKey="Fritz E">EA Fritz</name></author><author><name sortKey="Hensley, Le" uniqKey="Hensley L">LE Hensley</name></author><author><name sortKey="Jahrling, Pb" uniqKey="Jahrling P">PB Jahrling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheahan, T" uniqKey="Sheahan T">T Sheahan</name></author><author><name sortKey="Rockx, B" uniqKey="Rockx B">B Rockx</name></author><author><name sortKey="Donaldson, E" uniqKey="Donaldson E">E Donaldson</name></author><author><name sortKey="Sims, A" uniqKey="Sims A">A Sims</name></author><author><name sortKey="Pickles, R" uniqKey="Pickles R">R Pickles</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Caroline du Nord</li></region><settlement><li>Chapel Hill (Caroline du Nord)</li></settlement><orgName><li>Université de Caroline du Nord à Chapel Hill</li></orgName></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name></region><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Funkhouser, William" sort="Funkhouser, William" uniqKey="Funkhouser W" first="William" last="Funkhouser">William Funkhouser</name><name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name><name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name><name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name><name sortKey="Morrison, Thomas E" sort="Morrison, Thomas E" uniqKey="Morrison T" first="Thomas E." last="Morrison">Thomas E. Morrison</name><name sortKey="Morrison, Thomas E" sort="Morrison, Thomas E" uniqKey="Morrison T" first="Thomas E." last="Morrison">Thomas E. Morrison</name><name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name></country><country name="Japon"><noRegion><name sortKey="Uematsu, Satoshi" sort="Uematsu, Satoshi" uniqKey="Uematsu S" first="Satoshi" last="Uematsu">Satoshi Uematsu</name></noRegion><name sortKey="Akira, Shizou" sort="Akira, Shizou" uniqKey="Akira S" first="Shizou" last="Akira">Shizou Akira</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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