Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus
Identifieur interne : 000114 ( Main/Exploration ); précédent : 000113; suivant : 000115Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus
Auteurs : Hannah Kleine-Weber [Allemagne] ; Simon Schroeder [Allemagne] ; Nadine Krüger [Allemagne] ; Alexander Prokscha [Allemagne] ; Hassan Y. Naim [Allemagne] ; Marcel A. Müller [Allemagne, Russie] ; Christian Drosten [Allemagne] ; Stefan Pöhlmann [Allemagne] ; Markus Hoffmann [Allemagne]Source :
- Emerging Microbes & Infections [ 2222-1751 ] ; 2020.
Abstract
Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.
Url:
DOI: 10.1080/22221751.2020.1713705
PubMed: 31964246
PubMed Central: 7006675
Affiliations:
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Kleine-Weber</name><affiliation wicri:level="1"><nlm:aff id="AF1"><institution>Infection Biology Unit, German Primate Center</institution>, Göttingen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="AF2"><institution>Faculty of Biology and Psychology, University Göttingen</institution>, Göttingen,<institution>Germany</institution></nlm:aff></affiliation></author><author><name sortKey="Schroeder, Simon" sort="Schroeder, Simon" uniqKey="Schroeder S" first="Simon" last="Schroeder">Simon Schroeder</name><affiliation wicri:level="1"><nlm:aff id="AF3"><institution>Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kruger, Nadine" sort="Kruger, Nadine" uniqKey="Kruger N" first="Nadine" last="Krüger">Nadine Krüger</name><affiliation wicri:level="1"><nlm:aff id="AF4"><institution>Institute of Virology, University of Veterinary Medicine Hannover</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF5"><institution>Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Prokscha, Alexander" sort="Prokscha, Alexander" uniqKey="Prokscha A" first="Alexander" last="Prokscha">Alexander Prokscha</name><affiliation wicri:level="1"><nlm:aff id="AF6"><institution>Department of Physiological Chemistry, University of Veterinary Medicine Hannover</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Naim, Hassan Y" sort="Naim, Hassan Y" uniqKey="Naim H" first="Hassan Y." last="Naim">Hassan Y. Naim</name><affiliation wicri:level="1"><nlm:aff id="AF6"><institution>Department of Physiological Chemistry, University of Veterinary Medicine Hannover</institution>, Hannover,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name><affiliation wicri:level="1"><nlm:aff id="AF3"><institution>Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF7"><institution>German Centre for Infection Research, associated partner Charité</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF8"><institution>Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University</institution>, Moscow,<country>Russia</country></nlm:aff><country xml:lang="fr">Russie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="1"><nlm:aff id="AF3"><institution>Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AF7"><institution>German Centre for Infection Research, associated partner Charité</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pohlmann, Stefan" sort="Pohlmann, Stefan" uniqKey="Pohlmann S" first="Stefan" last="Pöhlmann">Stefan Pöhlmann</name><affiliation wicri:level="1"><nlm:aff id="AF1"><institution>Infection Biology Unit, German Primate Center</institution>, Göttingen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="AF2"><institution>Faculty of Biology and Psychology, University Göttingen</institution>, Göttingen,<institution>Germany</institution></nlm:aff></affiliation></author><author><name sortKey="Hoffmann, Markus" sort="Hoffmann, Markus" uniqKey="Hoffmann M" first="Markus" last="Hoffmann">Markus Hoffmann</name><affiliation wicri:level="1"><nlm:aff id="AF1"><institution>Infection Biology Unit, German Primate Center</institution>, Göttingen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Emerging Microbes & Infections</title><idno type="eISSN">2222-1751</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Adney, Dr" uniqKey="Adney D">DR Adney</name></author><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N van Doremalen</name></author><author><name sortKey="Brown, Vr" uniqKey="Brown V">VR Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Azhar, Ei" uniqKey="Azhar E">EI Azhar</name></author><author><name sortKey="El Kafrawy, Sa" uniqKey="El Kafrawy S">SA El-Kafrawy</name></author><author><name sortKey="Farraj, Sa" uniqKey="Farraj S">SA Farraj</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author><author><name sortKey="Al Dhahiry, Sh" uniqKey="Al Dhahiry S">SH Al Dhahiry</name></author><author><name sortKey="Reusken, Cb" uniqKey="Reusken C">CB Reusken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Farag, Ea" uniqKey="Farag E">EA Farag</name></author><author><name sortKey="Reusken, Cb" uniqKey="Reusken C">CB Reusken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Abdallat, Mm" uniqKey="Al Abdallat M">MM Al-Abdallat</name></author><author><name sortKey="Payne, Dc" uniqKey="Payne D">DC Payne</name></author><author><name sortKey="Alqasrawi, S" uniqKey="Alqasrawi S">S Alqasrawi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A Assiri</name></author><author><name sortKey="Mcgeer, A" uniqKey="Mcgeer A">A McGeer</name></author><author><name sortKey="Perl, Tm" uniqKey="Perl T">TM Perl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fagbo, Sf" uniqKey="Fagbo S">SF Fagbo</name></author><author><name sortKey="Skakni, L" uniqKey="Skakni L">L Skakni</name></author><author><name sortKey="Chu, Dk" uniqKey="Chu D">DK Chu</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Oboho, Ik" uniqKey="Oboho I">IK Oboho</name></author><author><name sortKey="Tomczyk, Sm" uniqKey="Tomczyk S">SM Tomczyk</name></author><author><name sortKey="Al Asmari, Am" uniqKey="Al Asmari A">AM Al-Asmari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, Hy" uniqKey="Park H">HY Park</name></author><author><name sortKey="Lee, Ej" uniqKey="Lee E">EJ Lee</name></author><author><name sortKey="Ryu, Yw" uniqKey="Ryu Y">YW Ryu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author><author><name sortKey="Meyer, B" uniqKey="Meyer B">B Meyer</name></author><author><name sortKey="Muller, Ma" uniqKey="Muller M">MA Muller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Widagdo, W" uniqKey="Widagdo W">W Widagdo</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Schipper, D" uniqKey="Schipper D">D Schipper</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Mou, H" uniqKey="Mou H">H Mou</name></author><author><name sortKey="Smits, Sl" uniqKey="Smits S">SL Smits</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, N" uniqKey="Wang N">N Wang</name></author><author><name sortKey="Shi, X" uniqKey="Shi X">X Shi</name></author><author><name sortKey="Jiang, L" uniqKey="Jiang L">L Jiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gierer, S" uniqKey="Gierer S">S Gierer</name></author><author><name sortKey="Bertram, S" uniqKey="Bertram S">S Bertram</name></author><author><name sortKey="Kaup, F" uniqKey="Kaup F">F Kaup</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qian, Z" uniqKey="Qian Z">Z Qian</name></author><author><name sortKey="Dominguez, Sr" uniqKey="Dominguez S">SR Dominguez</name></author><author><name sortKey="Holmes, Kv" uniqKey="Holmes K">KV. 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Müller</name><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name><name sortKey="Naim, Hassan Y" sort="Naim, Hassan Y" uniqKey="Naim H" first="Hassan Y." last="Naim">Hassan Y. Naim</name><name sortKey="Pohlmann, Stefan" sort="Pohlmann, Stefan" uniqKey="Pohlmann S" first="Stefan" last="Pöhlmann">Stefan Pöhlmann</name><name sortKey="Prokscha, Alexander" sort="Prokscha, Alexander" uniqKey="Prokscha A" first="Alexander" last="Prokscha">Alexander Prokscha</name><name sortKey="Schroeder, Simon" sort="Schroeder, Simon" uniqKey="Schroeder S" first="Simon" last="Schroeder">Simon Schroeder</name></country><country name="Russie"><noRegion><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A." last="Müller">Marcel A. Müller</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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