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Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses

Identifieur interne : 000006 ( 1957/Analysis ); précédent : 000005; suivant : 000007

Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses

Auteurs : Haixia Xiao [République populaire de Chine] ; Tianling Guo [République populaire de Chine] ; Mi Yang [République populaire de Chine] ; Jianxun Qi [République populaire de Chine] ; Chaobin Huang [République populaire de Chine] ; Yuanyuan Hong [République populaire de Chine] ; Jinjin Gu [République populaire de Chine] ; Xuefei Pang [République populaire de Chine] ; William Jun Liu [République populaire de Chine] ; Ruchao Peng [République populaire de Chine] ; John Mccauley ; Yuhai Bi [République populaire de Chine] ; Shihua Li [République populaire de Chine] ; Junxia Feng [République populaire de Chine] ; Hailiang Zhang [République populaire de Chine] ; Xupei Zhang [République populaire de Chine] ; Xishan Lu [République populaire de Chine] ; Jinghua Yan [République populaire de Chine] ; Liling Chen [République populaire de Chine] ; Yi Shi [République populaire de Chine] ; Weizhi Chen [République populaire de Chine] ; George Fu Gao [République populaire de Chine]

Source :

RBID : PMC:6465249

Abstract

The isolation of human monoclonal antibodies with broadly neutralizing breadth can provide a promising countermeasure for influenza A viruses infection. Most broadly neutralizing antibodies against influenza A viruses bind to the conserved stem region or the receptor-binding cavity of hemagglutinin and the interaction is dominated by the heavy chain. The light chain, however, contributes few or no direct contacts to the antigen. Here we report an H3-clade neutralizing human monoclonal antibody, AF4H1K1, which recognizes the hemagglutinin glycoproteins of all group 2 influenza A viruses. This human monoclonal antibody has been obtained through the screening by pairing different heavy and light chains from an H7N9-infected patient based on the next-generation sequencing technology. Further structural studies revealed that light chains modulate the neutralizing spectrum by affecting the local conformation of heavy chains, instead of direct interaction with the antigen. These findings provide important clues to understand the molecular basis of light chains in antigen recognition and to explore the strategies in particular of the use of light chain modification to develop broadly protective monoclonal antibodies against influenza A viruses and other emerging viruses.


Url:
DOI: 10.1038/s41421-019-0086-x
PubMed: 30993000
PubMed Central: 6465249


Affiliations:


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PMC:6465249

Le document en format XML

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<name sortKey="Lu, Xishan" sort="Lu, Xishan" uniqKey="Lu X" first="Xishan" last="Lu">Xishan Lu</name>
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Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
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<affiliation wicri:level="1">
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<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0000 9735 6249</institution-id>
<institution-id institution-id-type="GRID">grid.413109.e</institution-id>
<institution>College of Biotechnology,</institution>
<institution>Tianjin University of Science and Technology,</institution>
</institution-wrap>
Tianjin, 300457 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Tianjin</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zhang, Xupei" sort="Zhang, Xupei" uniqKey="Zhang X" first="Xupei" last="Zhang">Xupei Zhang</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
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<institution-id institution-id-type="ISNI">0000 0004 1763 3963</institution-id>
<institution-id institution-id-type="GRID">grid.458513.e</institution-id>
<institution>Laboraroty of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Tianjin, 300308 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Tianjin</wicri:regionArea>
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<affiliation wicri:level="1">
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<institution-wrap>
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<institution>CAS Centre for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences (CAS), China Research Network,</institution>
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Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lu, Xishan" sort="Lu, Xishan" uniqKey="Lu X" first="Xishan" last="Lu">Xishan Lu</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
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<institution-id institution-id-type="ISNI">0000 0004 1763 3963</institution-id>
<institution-id institution-id-type="GRID">grid.458513.e</institution-id>
<institution>Laboraroty of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Tianjin, 300308 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Tianjin</wicri:regionArea>
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<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000000119573309</institution-id>
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<institution>CAS Centre for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences (CAS), China Research Network,</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Yan, Jinghua" sort="Yan, Jinghua" uniqKey="Yan J" first="Jinghua" last="Yan">Jinghua Yan</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff8">
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<institution-id institution-id-type="ISNI">0000 0004 0627 1442</institution-id>
<institution-id institution-id-type="GRID">grid.458488.d</institution-id>
<institution>CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Chen, Liling" sort="Chen, Liling" uniqKey="Chen L" first="Liling" last="Chen">Liling Chen</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff9">Suzhou Centre for Disease Control and Prevention, Suzhou, 215004 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Suzhou Centre for Disease Control and Prevention, Suzhou</wicri:regionArea>
<wicri:noRegion>Suzhou</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Shi, Yi" sort="Shi, Yi" uniqKey="Shi Y" first="Yi" last="Shi">Yi Shi</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000000119573309</institution-id>
<institution-id institution-id-type="GRID">grid.9227.e</institution-id>
<institution>CAS Centre for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences (CAS), China Research Network,</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="Aff3">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 0627 1442</institution-id>
<institution-id institution-id-type="GRID">grid.458488.d</institution-id>
<institution>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Chen, Weizhi" sort="Chen, Weizhi" uniqKey="Chen W" first="Weizhi" last="Chen">Weizhi Chen</name>
<affiliation wicri:level="3">
<nlm:aff id="Aff4">GENEWIZ China, Beijing, 102206 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>GENEWIZ China, Beijing</wicri:regionArea>
<placeName>
<settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Gao, George Fu" sort="Gao, George Fu" uniqKey="Gao G" first="George Fu" last="Gao">George Fu Gao</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
<institution-wrap>
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<institution>Laboraroty of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Tianjin, 300308 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Tianjin</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="Aff2">
<institution-wrap>
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<institution-id institution-id-type="GRID">grid.9227.e</institution-id>
<institution>CAS Centre for Influenza Research and Early-Warning (CASCIRE), Chinese Academy of Sciences (CAS), China Research Network,</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="Aff3">
<institution-wrap>
<institution-id institution-id-type="ISNI">0000 0004 0627 1442</institution-id>
<institution-id institution-id-type="GRID">grid.458488.d</institution-id>
<institution>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS),</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Cell Discovery</title>
<idno type="eISSN">2056-5968</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
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<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p id="Par1">The isolation of human monoclonal antibodies with broadly neutralizing breadth can provide a promising countermeasure for influenza A viruses infection. Most broadly neutralizing antibodies against influenza A viruses bind to the conserved stem region or the receptor-binding cavity of hemagglutinin and the interaction is dominated by the heavy chain. The light chain, however, contributes few or no direct contacts to the antigen. Here we report an H3-clade neutralizing human monoclonal antibody, AF4H1K1, which recognizes the hemagglutinin glycoproteins of all group 2 influenza A viruses. This human monoclonal antibody has been obtained through the screening by pairing different heavy and light chains from an H7N9-infected patient based on the next-generation sequencing technology. Further structural studies revealed that light chains modulate the neutralizing spectrum by affecting the local conformation of heavy chains, instead of direct interaction with the antigen. These findings provide important clues to understand the molecular basis of light chains in antigen recognition and to explore the strategies in particular of the use of light chain modification to develop broadly protective monoclonal antibodies against influenza A viruses and other emerging viruses.</p>
</div>
</front>
<back>
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<affiliations>
<list>
<country>
<li>République populaire de Chine</li>
</country>
<settlement>
<li>Pékin</li>
</settlement>
</list>
<tree>
<noCountry>
<name sortKey="Mccauley, John" sort="Mccauley, John" uniqKey="Mccauley J" first="John" last="Mccauley">John Mccauley</name>
</noCountry>
<country name="République populaire de Chine">
<noRegion>
<name sortKey="Xiao, Haixia" sort="Xiao, Haixia" uniqKey="Xiao H" first="Haixia" last="Xiao">Haixia Xiao</name>
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<name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<name sortKey="Chen, Liling" sort="Chen, Liling" uniqKey="Chen L" first="Liling" last="Chen">Liling Chen</name>
<name sortKey="Chen, Weizhi" sort="Chen, Weizhi" uniqKey="Chen W" first="Weizhi" last="Chen">Weizhi Chen</name>
<name sortKey="Feng, Junxia" sort="Feng, Junxia" uniqKey="Feng J" first="Junxia" last="Feng">Junxia Feng</name>
<name sortKey="Feng, Junxia" sort="Feng, Junxia" uniqKey="Feng J" first="Junxia" last="Feng">Junxia Feng</name>
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<name sortKey="Gao, George Fu" sort="Gao, George Fu" uniqKey="Gao G" first="George Fu" last="Gao">George Fu Gao</name>
<name sortKey="Gao, George Fu" sort="Gao, George Fu" uniqKey="Gao G" first="George Fu" last="Gao">George Fu Gao</name>
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<name sortKey="Guo, Tianling" sort="Guo, Tianling" uniqKey="Guo T" first="Tianling" last="Guo">Tianling Guo</name>
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<name sortKey="Li, Shihua" sort="Li, Shihua" uniqKey="Li S" first="Shihua" last="Li">Shihua Li</name>
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<name sortKey="Qi, Jianxun" sort="Qi, Jianxun" uniqKey="Qi J" first="Jianxun" last="Qi">Jianxun Qi</name>
<name sortKey="Shi, Yi" sort="Shi, Yi" uniqKey="Shi Y" first="Yi" last="Shi">Yi Shi</name>
<name sortKey="Shi, Yi" sort="Shi, Yi" uniqKey="Shi Y" first="Yi" last="Shi">Yi Shi</name>
<name sortKey="Xiao, Haixia" sort="Xiao, Haixia" uniqKey="Xiao H" first="Haixia" last="Xiao">Haixia Xiao</name>
<name sortKey="Yan, Jinghua" sort="Yan, Jinghua" uniqKey="Yan J" first="Jinghua" last="Yan">Jinghua Yan</name>
<name sortKey="Yang, Mi" sort="Yang, Mi" uniqKey="Yang M" first="Mi" last="Yang">Mi Yang</name>
<name sortKey="Yang, Mi" sort="Yang, Mi" uniqKey="Yang M" first="Mi" last="Yang">Mi Yang</name>
<name sortKey="Yang, Mi" sort="Yang, Mi" uniqKey="Yang M" first="Mi" last="Yang">Mi Yang</name>
<name sortKey="Zhang, Hailiang" sort="Zhang, Hailiang" uniqKey="Zhang H" first="Hailiang" last="Zhang">Hailiang Zhang</name>
<name sortKey="Zhang, Hailiang" sort="Zhang, Hailiang" uniqKey="Zhang H" first="Hailiang" last="Zhang">Hailiang Zhang</name>
<name sortKey="Zhang, Hailiang" sort="Zhang, Hailiang" uniqKey="Zhang H" first="Hailiang" last="Zhang">Hailiang Zhang</name>
<name sortKey="Zhang, Xupei" sort="Zhang, Xupei" uniqKey="Zhang X" first="Xupei" last="Zhang">Xupei Zhang</name>
<name sortKey="Zhang, Xupei" sort="Zhang, Xupei" uniqKey="Zhang X" first="Xupei" last="Zhang">Xupei Zhang</name>
</country>
</tree>
</affiliations>
</record>

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