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Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity
Hand, foot, and mouth disease (HFMD) is a highly contagious disease that usually affects infants and young children (<5 years). HFMD outbreaks occur frequently in the Asia-Pacific region, and these outbreaks are associated with enormous healthcare and socioeconomic burden. There is currently no s...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545151/ https://www.ncbi.nlm.nih.gov/pubmed/33101238 http://dx.doi.org/10.3389/fmicb.2020.562768 |
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author | Phanthong, Siratcha Densumite, Jaslan Seesuay, Watee Thanongsaksrikul, Jeeraphong Teimoori, Salma Sookrung, Nitat Poovorawan, Yong Onvimala, Napa Guntapong, Ratigorn Pattanapanyasat, Kovit Chaicumpa, Wanpen |
author_facet | Phanthong, Siratcha Densumite, Jaslan Seesuay, Watee Thanongsaksrikul, Jeeraphong Teimoori, Salma Sookrung, Nitat Poovorawan, Yong Onvimala, Napa Guntapong, Ratigorn Pattanapanyasat, Kovit Chaicumpa, Wanpen |
author_sort | Phanthong, Siratcha |
collection | PubMed |
description | Hand, foot, and mouth disease (HFMD) is a highly contagious disease that usually affects infants and young children (<5 years). HFMD outbreaks occur frequently in the Asia-Pacific region, and these outbreaks are associated with enormous healthcare and socioeconomic burden. There is currently no specific antiviral agent to treat HFMD and/or the severe complications that are frequently associated with the enterovirus of serotype EV71. Therefore, the development of a broadly effective and safe anti-enterovirus agent is an existential necessity. In this study, human single-chain antibodies (HuscFvs) specific to the EV71-internal capsid protein (VP4) were generated using phage display technology. VP4 specific-HuscFvs were linked to cell penetrating peptides to make them cell penetrable HuscFvs (transbodies), and readily accessible to the intracellular target. The transbodies, as well as the original HuscFvs that were tested, entered the enterovirus-infected cells, bound to intracellular VP4, and inhibited replication of EV71 across subgenotypes A, B, and C, and coxsackieviruses CVA16 and CVA6. The antibodies also enhanced the antiviral response of the virus-infected cells. Computerized simulation, indirect and competitive ELISAs, and experiments on cells infected with EV71 particles to which the VP4 and VP1-N-terminus were surface-exposed (i.e., A-particles that don’t require receptor binding for infection) indicated that the VP4 specific-antibodies inhibit virus replication by interfering with the VP4-N-terminus, which is important for membrane pore formation and virus genome release leading to less production of virus proteins, less infectious virions, and restoration of host innate immunity. The antibodies may inhibit polyprotein/intermediate protein processing and cause sterically strained configurations of the capsid pentamers, which impairs virus morphogenesis. These antibodies should be further investigated for application as a safe and broadly effective HFMD therapy. |
format | Online Article Text |
id | pubmed-7545151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75451512020-10-22 Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity Phanthong, Siratcha Densumite, Jaslan Seesuay, Watee Thanongsaksrikul, Jeeraphong Teimoori, Salma Sookrung, Nitat Poovorawan, Yong Onvimala, Napa Guntapong, Ratigorn Pattanapanyasat, Kovit Chaicumpa, Wanpen Front Microbiol Microbiology Hand, foot, and mouth disease (HFMD) is a highly contagious disease that usually affects infants and young children (<5 years). HFMD outbreaks occur frequently in the Asia-Pacific region, and these outbreaks are associated with enormous healthcare and socioeconomic burden. There is currently no specific antiviral agent to treat HFMD and/or the severe complications that are frequently associated with the enterovirus of serotype EV71. Therefore, the development of a broadly effective and safe anti-enterovirus agent is an existential necessity. In this study, human single-chain antibodies (HuscFvs) specific to the EV71-internal capsid protein (VP4) were generated using phage display technology. VP4 specific-HuscFvs were linked to cell penetrating peptides to make them cell penetrable HuscFvs (transbodies), and readily accessible to the intracellular target. The transbodies, as well as the original HuscFvs that were tested, entered the enterovirus-infected cells, bound to intracellular VP4, and inhibited replication of EV71 across subgenotypes A, B, and C, and coxsackieviruses CVA16 and CVA6. The antibodies also enhanced the antiviral response of the virus-infected cells. Computerized simulation, indirect and competitive ELISAs, and experiments on cells infected with EV71 particles to which the VP4 and VP1-N-terminus were surface-exposed (i.e., A-particles that don’t require receptor binding for infection) indicated that the VP4 specific-antibodies inhibit virus replication by interfering with the VP4-N-terminus, which is important for membrane pore formation and virus genome release leading to less production of virus proteins, less infectious virions, and restoration of host innate immunity. The antibodies may inhibit polyprotein/intermediate protein processing and cause sterically strained configurations of the capsid pentamers, which impairs virus morphogenesis. These antibodies should be further investigated for application as a safe and broadly effective HFMD therapy. Frontiers Media S.A. 2020-09-25 /pmc/articles/PMC7545151/ /pubmed/33101238 http://dx.doi.org/10.3389/fmicb.2020.562768 Text en Copyright © 2020 Phanthong, Densumite, Seesuay, Thanongsaksrikul, Teimoori, Sookrung, Poovorawan, Onvimala, Guntapong, Pattanapanyasat and Chaicumpa. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Phanthong, Siratcha Densumite, Jaslan Seesuay, Watee Thanongsaksrikul, Jeeraphong Teimoori, Salma Sookrung, Nitat Poovorawan, Yong Onvimala, Napa Guntapong, Ratigorn Pattanapanyasat, Kovit Chaicumpa, Wanpen Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title | Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title_full | Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title_fullStr | Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title_full_unstemmed | Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title_short | Human Antibodies to VP4 Inhibit Replication of Enteroviruses Across Subgenotypes and Serotypes, and Enhance Host Innate Immunity |
title_sort | human antibodies to vp4 inhibit replication of enteroviruses across subgenotypes and serotypes, and enhance host innate immunity |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545151/ https://www.ncbi.nlm.nih.gov/pubmed/33101238 http://dx.doi.org/10.3389/fmicb.2020.562768 |
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