Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neut...
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| creator | Li, Liushuai Chong, Tingting Peng, Lu Liu, Yajie Rao, Guibo Fu, Yan Shu, Yanni Shen, Jiamei Xiao, Qinghong Liu, Jia Li, Jiang Deng, Fei Yan, Bing Hu, Zhihong Cao, Sheng Wang, Manli |
| description | Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins. |
| doi_str_mv | 10.1371/journal.ppat.1011948 |
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Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1011948</identifier><identifier>PMID: 38300972</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Biology and Life Sciences ; Crimean hemorrhagic fever ; Cryoelectron Microscopy ; Drug dosages ; Electron microscopy ; Epitopes ; Fever ; Glycoproteins ; Hemorrhagic Fever Virus, Crimean-Congo - genetics ; Hemorrhagic Fever, Crimean ; Humans ; Infections ; Infectious diseases ; Medicine and Health Sciences ; Membrane fusion ; Mice ; Monoclonal antibodies ; Neutralization ; Neutralizing ; Physical Sciences ; Proteins ; Research and Analysis Methods ; RNA polymerase ; Spleen ; Survival ; Survival analysis ; Viral infections ; Viruses</subject><ispartof>PLoS pathogens, 2024-02, Vol.20 (2), p.e1011948-e1011948</ispartof><rights>Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2024 Li et al 2024 Li et al</rights><rights>2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-29657204b9f8b4820fad6b108b803f9cda4929285945aaeb4b552c03109615dd3</citedby><cites>FETCH-LOGICAL-c527t-29657204b9f8b4820fad6b108b803f9cda4929285945aaeb4b552c03109615dd3</cites><orcidid>0000-0001-8701-3530</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863865/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10863865/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23849,27907,27908,53774,53776,79351,79352</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38300972$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Hartman, Amy L.</contributor><creatorcontrib>Li, Liushuai</creatorcontrib><creatorcontrib>Chong, Tingting</creatorcontrib><creatorcontrib>Peng, Lu</creatorcontrib><creatorcontrib>Liu, Yajie</creatorcontrib><creatorcontrib>Rao, Guibo</creatorcontrib><creatorcontrib>Fu, Yan</creatorcontrib><creatorcontrib>Shu, Yanni</creatorcontrib><creatorcontrib>Shen, Jiamei</creatorcontrib><creatorcontrib>Xiao, Qinghong</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Li, Jiang</creatorcontrib><creatorcontrib>Deng, Fei</creatorcontrib><creatorcontrib>Yan, Bing</creatorcontrib><creatorcontrib>Hu, Zhihong</creatorcontrib><creatorcontrib>Cao, Sheng</creatorcontrib><creatorcontrib>Wang, Manli</creatorcontrib><title>Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.</description><subject>Animals</subject><subject>Antibodies, Monoclonal</subject><subject>Antibodies, Neutralizing</subject><subject>Biology and Life Sciences</subject><subject>Crimean hemorrhagic fever</subject><subject>Cryoelectron Microscopy</subject><subject>Drug dosages</subject><subject>Electron microscopy</subject><subject>Epitopes</subject><subject>Fever</subject><subject>Glycoproteins</subject><subject>Hemorrhagic Fever Virus, Crimean-Congo - genetics</subject><subject>Hemorrhagic Fever, Crimean</subject><subject>Humans</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Medicine and Health Sciences</subject><subject>Membrane fusion</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>Neutralization</subject><subject>Neutralizing</subject><subject>Physical Sciences</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>RNA polymerase</subject><subject>Spleen</subject><subject>Survival</subject><subject>Survival analysis</subject><subject>Viral infections</subject><subject>Viruses</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUktv1DAYjBCIlsI_QGCJC5csfj9OqFq1pVIFFzhbjuNkvUrsYCcrwa_Hy6ZVizj5kz0z_mY0VfUWwQ0iAn3axyUFM2ymycwbBBFSVD6rzhFjpBZE0OeP5rPqVc57CCkiiL-szogkECqBz6vxq1vmZAb_24cejDFEO8QiC0yYfRNb7zIwvfEhz2DeOXBjQbdkHwMYYpxAcv1xjh3YJj86E-ptDH0EOzfGlHam9wXvDi6Bg09Lfl296MyQ3Zv1vKh-XF99336p777d3G4v72rLsJhrrDgTGNJGdbKhEsPOtLxBUDYSkk7Z1lCFFZZMUWaMa2jDGLaQIKg4Ym1LLqr3J91piFmvSWVNIFdIYil4QdyeEG00ez2V5U36paPx-u9FTL02afZ2cJpbRShrhOWmoxhziWxHFSdMCNcxrIrW5_W3pRlda104JvpE9OlL8Dvdx4MujjiRnBWFj6tCij8Xl2c9-mzdMJjg4pJ1Mcuh4CWXAv3wD_T_9ugJZVPMObnuYRsE9bE-9yx9rI9e61No7x47eSDd94X8AZFCw88</recordid><startdate>202402</startdate><enddate>202402</enddate><creator>Li, Liushuai</creator><creator>Chong, Tingting</creator><creator>Peng, Lu</creator><creator>Liu, Yajie</creator><creator>Rao, Guibo</creator><creator>Fu, Yan</creator><creator>Shu, Yanni</creator><creator>Shen, Jiamei</creator><creator>Xiao, Qinghong</creator><creator>Liu, Jia</creator><creator>Li, Jiang</creator><creator>Deng, Fei</creator><creator>Yan, Bing</creator><creator>Hu, Zhihong</creator><creator>Cao, Sheng</creator><creator>Wang, Manli</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-8701-3530</orcidid></search><sort><creationdate>202402</creationdate><title>Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus</title><author>Li, Liushuai ; Chong, Tingting ; Peng, Lu ; Liu, Yajie ; Rao, Guibo ; Fu, Yan ; Shu, Yanni ; Shen, Jiamei ; Xiao, Qinghong ; Liu, Jia ; Li, Jiang ; Deng, Fei ; Yan, Bing ; Hu, Zhihong ; Cao, Sheng ; Wang, Manli</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-29657204b9f8b4820fad6b108b803f9cda4929285945aaeb4b552c03109615dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal</topic><topic>Antibodies, Neutralizing</topic><topic>Biology and Life Sciences</topic><topic>Crimean hemorrhagic fever</topic><topic>Cryoelectron Microscopy</topic><topic>Drug dosages</topic><topic>Electron microscopy</topic><topic>Epitopes</topic><topic>Fever</topic><topic>Glycoproteins</topic><topic>Hemorrhagic Fever Virus, Crimean-Congo - genetics</topic><topic>Hemorrhagic Fever, Crimean</topic><topic>Humans</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Medicine and Health Sciences</topic><topic>Membrane fusion</topic><topic>Mice</topic><topic>Monoclonal antibodies</topic><topic>Neutralization</topic><topic>Neutralizing</topic><topic>Physical Sciences</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>RNA polymerase</topic><topic>Spleen</topic><topic>Survival</topic><topic>Survival analysis</topic><topic>Viral infections</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Liushuai</creatorcontrib><creatorcontrib>Chong, Tingting</creatorcontrib><creatorcontrib>Peng, Lu</creatorcontrib><creatorcontrib>Liu, Yajie</creatorcontrib><creatorcontrib>Rao, Guibo</creatorcontrib><creatorcontrib>Fu, Yan</creatorcontrib><creatorcontrib>Shu, Yanni</creatorcontrib><creatorcontrib>Shen, Jiamei</creatorcontrib><creatorcontrib>Xiao, Qinghong</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Li, Jiang</creatorcontrib><creatorcontrib>Deng, Fei</creatorcontrib><creatorcontrib>Yan, Bing</creatorcontrib><creatorcontrib>Hu, Zhihong</creatorcontrib><creatorcontrib>Cao, Sheng</creatorcontrib><creatorcontrib>Wang, Manli</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Coronavirus Research Database</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Liushuai</au><au>Chong, Tingting</au><au>Peng, Lu</au><au>Liu, Yajie</au><au>Rao, Guibo</au><au>Fu, Yan</au><au>Shu, Yanni</au><au>Shen, Jiamei</au><au>Xiao, Qinghong</au><au>Liu, Jia</au><au>Li, Jiang</au><au>Deng, Fei</au><au>Yan, Bing</au><au>Hu, Zhihong</au><au>Cao, Sheng</au><au>Wang, Manli</au><au>Hartman, Amy L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2024-02</date><risdate>2024</risdate><volume>20</volume><issue>2</issue><spage>e1011948</spage><epage>e1011948</epage><pages>e1011948-e1011948</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>38300972</pmid><doi>10.1371/journal.ppat.1011948</doi><orcidid>https://orcid.org/0000-0001-8701-3530</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies, Monoclonal Antibodies, Neutralizing Biology and Life Sciences Crimean hemorrhagic fever Cryoelectron Microscopy Drug dosages Electron microscopy Epitopes Fever Glycoproteins Hemorrhagic Fever Virus, Crimean-Congo - genetics Hemorrhagic Fever, Crimean Humans Infections Infectious diseases Medicine and Health Sciences Membrane fusion Mice Monoclonal antibodies Neutralization Neutralizing Physical Sciences Proteins Research and Analysis Methods RNA polymerase Spleen Survival Survival analysis Viral infections Viruses |
| title | Neutralizing monoclonal antibodies against the Gc fusion loop region of Crimean-Congo hemorrhagic fever virus |
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