MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells
Identifieur interne : 000911 ( Main/Exploration ); précédent : 000910; suivant : 000912MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells
Auteurs : Yu Cong [États-Unis] ; Brit J. Hart [États-Unis] ; Robin Gross [États-Unis] ; Huanying Zhou [États-Unis] ; Matthew Frieman [États-Unis] ; Laura Bollinger [États-Unis] ; Jiro Wada [États-Unis] ; Lisa E. Hensley [États-Unis] ; Peter B. Jahrling [États-Unis] ; Julie Dyall [États-Unis] ; Michael R. Holbrook [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2018.
Descripteurs français
- KwdFr :
- Agrément de médicaments, Animaux, Antiviraux (usage thérapeutique), Cellules Vero, Cellules cultivées, Cellules présentatrices d'antigène (), Cellules présentatrices d'antigène (physiologie), Coronavirus du syndrome respiratoire du Moyen-Orient (), Humains, Infections à coronavirus (immunologie), Infections à coronavirus (traitement médicamenteux), Macrophages (), Macrophages (physiologie), Monocytes (physiologie), Résultat thérapeutique, Évaluation préclinique de médicament.
- MESH :
- immunologie : Infections à coronavirus.
- physiologie : Cellules présentatrices d'antigène, Macrophages, Monocytes.
- traitement médicamenteux : Infections à coronavirus.
- usage thérapeutique : Antiviraux.
- Agrément de médicaments, Animaux, Cellules Vero, Cellules cultivées, Cellules présentatrices d'antigène, Coronavirus du syndrome respiratoire du Moyen-Orient, Humains, Macrophages, Résultat thérapeutique, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Animals, Antigen-Presenting Cells (drug effects), Antigen-Presenting Cells (physiology), Antiviral Agents (therapeutic use), Cells, Cultured, Chlorocebus aethiops, Coronavirus Infections (drug therapy), Coronavirus Infections (immunology), Drug Approval, Drug Evaluation, Preclinical, Humans, Macrophages (drug effects), Macrophages (physiology), Middle East Respiratory Syndrome Coronavirus (drug effects), Monocytes (physiology), Treatment Outcome, Vero Cells.
- MESH :
- chemical , therapeutic use : Antiviral Agents.
- drug effects : Antigen-Presenting Cells, Macrophages, Middle East Respiratory Syndrome Coronavirus.
- drug therapy : Coronavirus Infections.
- immunology : Coronavirus Infections.
- physiology : Antigen-Presenting Cells, Macrophages, Monocytes.
- Animals, Cells, Cultured, Chlorocebus aethiops, Drug Approval, Drug Evaluation, Preclinical, Humans, Treatment Outcome, Vero Cells.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) presents an emerging threat to public health worldwide by causing severe respiratory disease in humans with high virulence and case fatality rate (about 35%) since 2012. Little is known about the pathogenesis and innate antiviral response in primary human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) upon MERS-CoV infection. In this study, we assessed MERS-CoV replication as well as induction of inflammatory cytokines and chemokines in MDMs and immature and mature MDDCs. Immature MDDCs and MDMs were permissive for MERS-CoV infection, while mature MDDCs were not, with stimulation of proinflammatory cytokine and chemokine upregulation in MDMs, but not in MDDCs. To further evaluate the antiviral activity of well-defined drugs in primary antigen presenting cells (APCs), three compounds (chloroquine, chlorpromazine and toremifine), each with broad-spectrum antiviral activity in immortalized cell lines, were evaluated in MDMs and MDDCs to determine their antiviral effect on MERS-CoV infection. While chloroquine was not active in these primary cells, chlorpromazine showed strong anti-MERS-CoV activity, but it was associated with high cytotoxicity narrowing the potential window for drug utilization. Unlike in established cells, toremifene had marginal activity when tested in antigen presenting cells, with high apparent cytotoxicity, also limiting its potential as a therapeutic option. These results demonstrate the value of testing drugs in primary cells, in addition to established cell lines, before initiating preclinical or clinical studies for MERS treatment and the importance of carefully assessing cytotoxicity in drug screen assays. Furthermore, these studies also highlight the role of APCs in stimulating a robust protective immune response to MERS-CoV infection.
Url:
DOI: 10.1371/journal.pone.0194868
PubMed: 29566060
PubMed Central: 5864050
Affiliations:
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Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hart, Brit J" sort="Hart, Brit J" uniqKey="Hart B" first="Brit J." last="Hart">Brit J. Hart</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Gross, Robin" sort="Gross, Robin" uniqKey="Gross R" first="Robin" last="Gross">Robin Gross</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. 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Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Wada, Jiro" sort="Wada, Jiro" uniqKey="Wada J" first="Jiro" last="Wada">Jiro Wada</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hensley, Lisa E" sort="Hensley, Lisa E" uniqKey="Hensley L" first="Lisa E." last="Hensley">Lisa E. Hensley</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Jahrling, Peter B" sort="Jahrling, Peter B" uniqKey="Jahrling P" first="Peter B." last="Jahrling">Peter B. Jahrling</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Emerging Viral Pathogen Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Emerging Viral Pathogen Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dyall, Julie" sort="Dyall, Julie" uniqKey="Dyall J" first="Julie" last="Dyall">Julie Dyall</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Holbrook, Michael R" sort="Holbrook, Michael R" uniqKey="Holbrook M" first="Michael R." last="Holbrook">Michael R. Holbrook</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Ft. Detrick, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antigen-Presenting Cells (drug effects)</term><term>Antigen-Presenting Cells (physiology)</term><term>Antiviral Agents (therapeutic use)</term><term>Cells, Cultured</term><term>Chlorocebus aethiops</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus Infections (immunology)</term><term>Drug Approval</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Macrophages (drug effects)</term><term>Macrophages (physiology)</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Monocytes (physiology)</term><term>Treatment Outcome</term><term>Vero Cells</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agrément de médicaments</term><term>Animaux</term><term>Antiviraux (usage thérapeutique)</term><term>Cellules Vero</term><term>Cellules cultivées</term><term>Cellules présentatrices d'antigène ()</term><term>Cellules présentatrices d'antigène (physiologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Humains</term><term>Infections à coronavirus (immunologie)</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Macrophages ()</term><term>Macrophages (physiologie)</term><term>Monocytes (physiologie)</term><term>Résultat thérapeutique</term><term>Évaluation préclinique de médicament</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Antigen-Presenting Cells</term><term>Macrophages</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Cellules présentatrices d'antigène</term><term>Macrophages</term><term>Monocytes</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Antigen-Presenting Cells</term><term>Macrophages</term><term>Monocytes</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Chlorocebus aethiops</term><term>Drug Approval</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Treatment Outcome</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agrément de médicaments</term><term>Animaux</term><term>Cellules Vero</term><term>Cellules cultivées</term><term>Cellules présentatrices d'antigène</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Humains</term><term>Macrophages</term><term>Résultat thérapeutique</term><term>Évaluation préclinique de médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) presents an emerging threat to public health worldwide by causing severe respiratory disease in humans with high virulence and case fatality rate (about 35%) since 2012. Little is known about the pathogenesis and innate antiviral response in primary human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) upon MERS-CoV infection. In this study, we assessed MERS-CoV replication as well as induction of inflammatory cytokines and chemokines in MDMs and immature and mature MDDCs. Immature MDDCs and MDMs were permissive for MERS-CoV infection, while mature MDDCs were not, with stimulation of proinflammatory cytokine and chemokine upregulation in MDMs, but not in MDDCs. To further evaluate the antiviral activity of well-defined drugs in primary antigen presenting cells (APCs), three compounds (chloroquine, chlorpromazine and toremifine), each with broad-spectrum antiviral activity in immortalized cell lines, were evaluated in MDMs and MDDCs to determine their antiviral effect on MERS-CoV infection. While chloroquine was not active in these primary cells, chlorpromazine showed strong anti-MERS-CoV activity, but it was associated with high cytotoxicity narrowing the potential window for drug utilization. Unlike in established cells, toremifene had marginal activity when tested in antigen presenting cells, with high apparent cytotoxicity, also limiting its potential as a therapeutic option. These results demonstrate the value of testing drugs in primary cells, in addition to established cell lines, before initiating preclinical or clinical studies for MERS treatment and the importance of carefully assessing cytotoxicity in drug screen assays. 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name="Maryland"><name sortKey="Cong, Yu" sort="Cong, Yu" uniqKey="Cong Y" first="Yu" last="Cong">Yu Cong</name></region><name sortKey="Bollinger, Laura" sort="Bollinger, Laura" uniqKey="Bollinger L" first="Laura" last="Bollinger">Laura Bollinger</name><name sortKey="Dyall, Julie" sort="Dyall, Julie" uniqKey="Dyall J" first="Julie" last="Dyall">Julie Dyall</name><name sortKey="Frieman, Matthew" sort="Frieman, Matthew" uniqKey="Frieman M" first="Matthew" last="Frieman">Matthew Frieman</name><name sortKey="Gross, Robin" sort="Gross, Robin" uniqKey="Gross R" first="Robin" last="Gross">Robin Gross</name><name sortKey="Hart, Brit J" sort="Hart, Brit J" uniqKey="Hart B" first="Brit J." last="Hart">Brit J. Hart</name><name sortKey="Hensley, Lisa E" sort="Hensley, Lisa E" uniqKey="Hensley L" first="Lisa E." last="Hensley">Lisa E. Hensley</name><name sortKey="Holbrook, Michael R" sort="Holbrook, Michael R" uniqKey="Holbrook M" first="Michael R." last="Holbrook">Michael R. Holbrook</name><name sortKey="Jahrling, Peter B" sort="Jahrling, Peter B" uniqKey="Jahrling P" first="Peter B." last="Jahrling">Peter B. Jahrling</name><name sortKey="Jahrling, Peter B" sort="Jahrling, Peter B" uniqKey="Jahrling P" first="Peter B." last="Jahrling">Peter B. Jahrling</name><name sortKey="Wada, Jiro" sort="Wada, Jiro" uniqKey="Wada J" first="Jiro" last="Wada">Jiro Wada</name><name sortKey="Zhou, Huanying" sort="Zhou, Huanying" uniqKey="Zhou H" first="Huanying" last="Zhou">Huanying Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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