Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection

ABSTRACT Dengue is caused by infection with any one of four dengue viruses (DENV); the risk of severe disease appears to be enhanced by the cross-reactive or subneutralizing levels of antibody from a prior DENV infection. These antibodies opsonize DENV entry through the activating Fc gamma receptors...

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Autores principales:	Candice Y. Y. Chan, John Zhong Heng Low, Esther Shuyi Gan, Eugenia Ziying Ong, Summer Li-Xin Zhang, Hwee Cheng Tan, Xiaoran Chai, Sujoy Ghosh, Eng Eong Ooi, Kuan Rong Chan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	dengue virus host response virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bcfefce93ff84cbd9102d2fbf5e762ae
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spelling	oai:doaj.org-article:bcfefce93ff84cbd9102d2fbf5e762ae2021-11-15T15:27:32ZAntibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection10.1128/mSphere.00528-192379-5042https://doaj.org/article/bcfefce93ff84cbd9102d2fbf5e762ae2019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00528-19https://doaj.org/toc/2379-5042ABSTRACT Dengue is caused by infection with any one of four dengue viruses (DENV); the risk of severe disease appears to be enhanced by the cross-reactive or subneutralizing levels of antibody from a prior DENV infection. These antibodies opsonize DENV entry through the activating Fc gamma receptors (FcγR), instead of infection through canonical receptor-mediated endocytosis, to result in higher levels of DENV replication. However, whether the enhanced replication is solely due to more efficient FcγR-mediated DENV entry or is also through FcγR-mediated alteration of the host transcriptome response to favor DENV infection remains unclear. Indeed, more efficient viral entry through activation of the FcγR can result in an increased viral antigenic load within target cells and confound direct comparisons of the host transcriptome response under antibody-dependent and antibody-independent conditions. Herein, we show that, despite controlling for the viral antigenic load in primary monocytes, the antibody-dependent and non-antibody-dependent routes of DENV entry induce transcriptome responses that are remarkably different. Notably, antibody-dependent DENV entry upregulated DENV host dependency factors associated with RNA splicing, mitochondrial respiratory chain complexes, and vesicle trafficking. Additionally, supporting findings from other studies, antibody-dependent DENV entry impeded the downregulation of ribosomal genes caused by canonical receptor-mediated endocytosis to increase viral translation. Collectively, our findings support the notion that antibody-dependent DENV entry alters host responses that support the viral life cycle and that host responses to DENV need to be defined in the context of its entry pathway. IMPORTANCE Dengue virus is the most prevalent mosquito-borne viral infection globally, resulting in variable manifestations ranging from asymptomatic viremia to life-threatening shock and multiorgan failure. Previous studies have indicated that the risk of severe dengue in humans can be increased by a specific range of preexisting anti-dengue virus antibody titers, a phenomenon termed antibody-dependent enhancement. There is hence a need to understand how antibodies augment dengue virus infection compared to the alternative canonical receptor-mediated viral entry route. Herein, we show that, besides facilitating viral uptake, antibody-mediated entry increases the expression of early host dependency factors to promote viral infection; these factors include RNA splicing, mitochondrial respiratory chain complexes, vesicle trafficking, and ribosomal genes. These findings will enhance our understanding of how differences in entry pathways can affect host responses and offer opportunities to design therapeutics that can specifically inhibit antibody-dependent enhancement of dengue virus infection.Candice Y. Y. ChanJohn Zhong Heng LowEsther Shuyi GanEugenia Ziying OngSummer Li-Xin ZhangHwee Cheng TanXiaoran ChaiSujoy GhoshEng Eong OoiKuan Rong ChanAmerican Society for Microbiologyarticledengue virushost responsevirus-host interactionsMicrobiologyQR1-502ENmSphere, Vol 4, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	dengue virus host response virus-host interactions Microbiology QR1-502
spellingShingle	dengue virus host response virus-host interactions Microbiology QR1-502 Candice Y. Y. Chan John Zhong Heng Low Esther Shuyi Gan Eugenia Ziying Ong Summer Li-Xin Zhang Hwee Cheng Tan Xiaoran Chai Sujoy Ghosh Eng Eong Ooi Kuan Rong Chan Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
description	ABSTRACT Dengue is caused by infection with any one of four dengue viruses (DENV); the risk of severe disease appears to be enhanced by the cross-reactive or subneutralizing levels of antibody from a prior DENV infection. These antibodies opsonize DENV entry through the activating Fc gamma receptors (FcγR), instead of infection through canonical receptor-mediated endocytosis, to result in higher levels of DENV replication. However, whether the enhanced replication is solely due to more efficient FcγR-mediated DENV entry or is also through FcγR-mediated alteration of the host transcriptome response to favor DENV infection remains unclear. Indeed, more efficient viral entry through activation of the FcγR can result in an increased viral antigenic load within target cells and confound direct comparisons of the host transcriptome response under antibody-dependent and antibody-independent conditions. Herein, we show that, despite controlling for the viral antigenic load in primary monocytes, the antibody-dependent and non-antibody-dependent routes of DENV entry induce transcriptome responses that are remarkably different. Notably, antibody-dependent DENV entry upregulated DENV host dependency factors associated with RNA splicing, mitochondrial respiratory chain complexes, and vesicle trafficking. Additionally, supporting findings from other studies, antibody-dependent DENV entry impeded the downregulation of ribosomal genes caused by canonical receptor-mediated endocytosis to increase viral translation. Collectively, our findings support the notion that antibody-dependent DENV entry alters host responses that support the viral life cycle and that host responses to DENV need to be defined in the context of its entry pathway. IMPORTANCE Dengue virus is the most prevalent mosquito-borne viral infection globally, resulting in variable manifestations ranging from asymptomatic viremia to life-threatening shock and multiorgan failure. Previous studies have indicated that the risk of severe dengue in humans can be increased by a specific range of preexisting anti-dengue virus antibody titers, a phenomenon termed antibody-dependent enhancement. There is hence a need to understand how antibodies augment dengue virus infection compared to the alternative canonical receptor-mediated viral entry route. Herein, we show that, besides facilitating viral uptake, antibody-mediated entry increases the expression of early host dependency factors to promote viral infection; these factors include RNA splicing, mitochondrial respiratory chain complexes, vesicle trafficking, and ribosomal genes. These findings will enhance our understanding of how differences in entry pathways can affect host responses and offer opportunities to design therapeutics that can specifically inhibit antibody-dependent enhancement of dengue virus infection.
format	article
author	Candice Y. Y. Chan John Zhong Heng Low Esther Shuyi Gan Eugenia Ziying Ong Summer Li-Xin Zhang Hwee Cheng Tan Xiaoran Chai Sujoy Ghosh Eng Eong Ooi Kuan Rong Chan
author_facet	Candice Y. Y. Chan John Zhong Heng Low Esther Shuyi Gan Eugenia Ziying Ong Summer Li-Xin Zhang Hwee Cheng Tan Xiaoran Chai Sujoy Ghosh Eng Eong Ooi Kuan Rong Chan
author_sort	Candice Y. Y. Chan
title	Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
title_short	Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
title_full	Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
title_fullStr	Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
title_full_unstemmed	Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection
title_sort	antibody-dependent dengue virus entry modulates cell intrinsic responses for enhanced infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/bcfefce93ff84cbd9102d2fbf5e762ae
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Antibody-Dependent Dengue Virus Entry Modulates Cell Intrinsic Responses for Enhanced Infection

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