T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses

ABSTRACT The 2015–2016 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrated that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping...

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Autores principales:	Bobby Brooke Herrera, Wen-Yang Tsai, Carlos Brites, Estela Luz, Celia Pedroso, Jan Felix Drexler, Wei-Kung Wang, Phyllis J. Kanki
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Brazil dengue virus T cell immunity Zika virus nonstructural protein 3 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6c10ba21bab8448fafe27a256ff4c24c
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spelling	oai:doaj.org-article:6c10ba21bab8448fafe27a256ff4c24c2021-11-15T16:00:15ZT Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses10.1128/mBio.00755-182150-7511https://doaj.org/article/6c10ba21bab8448fafe27a256ff4c24c2018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00755-18https://doaj.org/toc/2150-7511ABSTRACT The 2015–2016 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrated that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping geographic distributions and have significant sequence similarities that can increase the potential for antibody and T cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent assays (ELISAs), we determined the serostatus of individuals living in a region of DENV and ZIKV endemicity in Brazil, identifying individuals with primary DENV (pDENV) and primary ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections; the presence of pDENV and pZIKV was further confirmed by neutralization tests. Development of an enzyme-linked immunosorbent spot (ELISPOT) assay for DENV and ZIKV structural and nonstructural (NS) protein antigens enabled us to distinguish infections by these viruses based on T cell responses and to characterize those responses. We found that gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) T cell responses to NS3 differentiated DENV and ZIKV infections with 94% sensitivity and 92% specificity. In general, we also showed that pDENV and sDENV cases and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns and that HIV-infected individuals show T cell responses that are lower than those shown by HIV-negative individuals. These results have important implications for DENV and ZIKV diagnostic and vaccine development and provide critical insights into the T cell response in individuals with multiple flaviviral infections. IMPORTANCE The potential for antibody and T cell cross-reactions to DENV and ZIKV, flaviviruses that cocirculate and can sequentially infect individuals, has complicated diagnostic and vaccine development. Our serological data show that antibodies to nonstructural protein 1 can distinguish sequential human infections by DENV and ZIKV. The development of a simple and inexpensive assay also enables the differentiation of DENV and ZIKV infections based on characterization of T cell responses. Our T cell data reveal strong response patterns that are similar in nature to those seen with individuals with one or multiple DENV infections and with individuals with only primary ZIKV infection and ZIKV-infected individuals with previous DENV exposure. The characterization of T cell responses in a serologically validated group of individuals is of relevance to the development of vaccines and immunotherapeutics against these global threats.Bobby Brooke HerreraWen-Yang TsaiCarlos BritesEstela LuzCelia PedrosoJan Felix DrexlerWei-Kung WangPhyllis J. KankiAmerican Society for MicrobiologyarticleBrazildengue virusT cell immunityZika virusnonstructural protein 3MicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Brazil dengue virus T cell immunity Zika virus nonstructural protein 3 Microbiology QR1-502
spellingShingle	Brazil dengue virus T cell immunity Zika virus nonstructural protein 3 Microbiology QR1-502 Bobby Brooke Herrera Wen-Yang Tsai Carlos Brites Estela Luz Celia Pedroso Jan Felix Drexler Wei-Kung Wang Phyllis J. Kanki T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
description	ABSTRACT The 2015–2016 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrated that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping geographic distributions and have significant sequence similarities that can increase the potential for antibody and T cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent assays (ELISAs), we determined the serostatus of individuals living in a region of DENV and ZIKV endemicity in Brazil, identifying individuals with primary DENV (pDENV) and primary ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections; the presence of pDENV and pZIKV was further confirmed by neutralization tests. Development of an enzyme-linked immunosorbent spot (ELISPOT) assay for DENV and ZIKV structural and nonstructural (NS) protein antigens enabled us to distinguish infections by these viruses based on T cell responses and to characterize those responses. We found that gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) T cell responses to NS3 differentiated DENV and ZIKV infections with 94% sensitivity and 92% specificity. In general, we also showed that pDENV and sDENV cases and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns and that HIV-infected individuals show T cell responses that are lower than those shown by HIV-negative individuals. These results have important implications for DENV and ZIKV diagnostic and vaccine development and provide critical insights into the T cell response in individuals with multiple flaviviral infections. IMPORTANCE The potential for antibody and T cell cross-reactions to DENV and ZIKV, flaviviruses that cocirculate and can sequentially infect individuals, has complicated diagnostic and vaccine development. Our serological data show that antibodies to nonstructural protein 1 can distinguish sequential human infections by DENV and ZIKV. The development of a simple and inexpensive assay also enables the differentiation of DENV and ZIKV infections based on characterization of T cell responses. Our T cell data reveal strong response patterns that are similar in nature to those seen with individuals with one or multiple DENV infections and with individuals with only primary ZIKV infection and ZIKV-infected individuals with previous DENV exposure. The characterization of T cell responses in a serologically validated group of individuals is of relevance to the development of vaccines and immunotherapeutics against these global threats.
format	article
author	Bobby Brooke Herrera Wen-Yang Tsai Carlos Brites Estela Luz Celia Pedroso Jan Felix Drexler Wei-Kung Wang Phyllis J. Kanki
author_facet	Bobby Brooke Herrera Wen-Yang Tsai Carlos Brites Estela Luz Celia Pedroso Jan Felix Drexler Wei-Kung Wang Phyllis J. Kanki
author_sort	Bobby Brooke Herrera
title	T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
title_short	T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
title_full	T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
title_fullStr	T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
title_full_unstemmed	T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses
title_sort	t cell responses to nonstructural protein 3 distinguish infections by dengue and zika viruses
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/6c10ba21bab8448fafe27a256ff4c24c
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T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses

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