Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus

ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 9...

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Autores principales:	Haihai Jiang, Weiyu Peng, Jianxun Qi, Yan Chai, Hao Song, Yuhai Bi, Pramila Rijal, Haiyuan Wang, Babayemi O. Oladejo, Jinhua Liu, Yi Shi, George F. Gao, Alain R. Townsend, Yan Wu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	influenza neuraminidase neutralizing antibody structure-based modification Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/819bb0fb960e4355a81c8a3995f7bb0b
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spelling	oai:doaj.org-article:819bb0fb960e4355a81c8a3995f7bb0b2021-11-15T16:19:09ZStructure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus10.1128/mBio.02315-202150-7511https://doaj.org/article/819bb0fb960e4355a81c8a3995f7bb0b2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02315-20https://doaj.org/toc/2150-7511ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain. IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.Haihai JiangWeiyu PengJianxun QiYan ChaiHao SongYuhai BiPramila RijalHaiyuan WangBabayemi O. OladejoJinhua LiuYi ShiGeorge F. GaoAlain R. TownsendYan WuAmerican Society for Microbiologyarticleinfluenzaneuraminidaseneutralizing antibodystructure-based modificationMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	influenza neuraminidase neutralizing antibody structure-based modification Microbiology QR1-502
spellingShingle	influenza neuraminidase neutralizing antibody structure-based modification Microbiology QR1-502 Haihai Jiang Weiyu Peng Jianxun Qi Yan Chai Hao Song Yuhai Bi Pramila Rijal Haiyuan Wang Babayemi O. Oladejo Jinhua Liu Yi Shi George F. Gao Alain R. Townsend Yan Wu Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
description	ABSTRACT Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain. IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.
format	article
author	Haihai Jiang Weiyu Peng Jianxun Qi Yan Chai Hao Song Yuhai Bi Pramila Rijal Haiyuan Wang Babayemi O. Oladejo Jinhua Liu Yi Shi George F. Gao Alain R. Townsend Yan Wu
author_facet	Haihai Jiang Weiyu Peng Jianxun Qi Yan Chai Hao Song Yuhai Bi Pramila Rijal Haiyuan Wang Babayemi O. Oladejo Jinhua Liu Yi Shi George F. Gao Alain R. Townsend Yan Wu
author_sort	Haihai Jiang
title	Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
title_short	Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
title_full	Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
title_fullStr	Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
title_full_unstemmed	Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus
title_sort	structure-based modification of an anti-neuraminidase human antibody restores protection efficacy against the drifted influenza virus
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/819bb0fb960e4355a81c8a3995f7bb0b
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Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus

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