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A fast-growing dengue virus mutant reveals a dual role of STING in response to infection

The four dengue viruses (DENVs) have evolved multiple mechanisms to ensure its survival. Among these mechanisms is the ability to regulate its replication rate, which may contribute to avoiding premature immune activation that limit infection dissemination: DENVs associated with dengue epidemics hav...

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Autores principales: Ng, Wy Ching, Kwek, Swee Sen, Sun, Bo, Yousefi, Meisam, Ong, Eugenia Z., Tan, Hwee Cheng, Puschnik, Andreas S., Chan, Kuan Rong, Ooi, Yaw Shin, Ooi, Eng Eong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748785/
https://www.ncbi.nlm.nih.gov/pubmed/36514984
http://dx.doi.org/10.1098/rsob.220227
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author Ng, Wy Ching
Kwek, Swee Sen
Sun, Bo
Yousefi, Meisam
Ong, Eugenia Z.
Tan, Hwee Cheng
Puschnik, Andreas S.
Chan, Kuan Rong
Ooi, Yaw Shin
Ooi, Eng Eong
author_facet Ng, Wy Ching
Kwek, Swee Sen
Sun, Bo
Yousefi, Meisam
Ong, Eugenia Z.
Tan, Hwee Cheng
Puschnik, Andreas S.
Chan, Kuan Rong
Ooi, Yaw Shin
Ooi, Eng Eong
author_sort Ng, Wy Ching
collection PubMed
description The four dengue viruses (DENVs) have evolved multiple mechanisms to ensure its survival. Among these mechanisms is the ability to regulate its replication rate, which may contribute to avoiding premature immune activation that limit infection dissemination: DENVs associated with dengue epidemics have shown slower replication rate than pre-epidemic strains. Correspondingly, wild-type DENVs replicate more slowly than their clinically attenuated derivatives. To understand how DENVs ‘make haste slowly’, we generated and screened for DENV2 mutants with accelerated replication that also induced high type-I interferon (IFN) expression in infected cells. We chanced upon a single NS2B-I114T amino acid substitution, in an otherwise highly conserved amino acid residue. Accelerated DENV2 replication damaged host DNA as mutant infection was dependent on host DNA damage repair factors, namely RAD21, EID3 and NEK5. DNA damage induced cGAS/STING signalling and activated early type-I IFN response that inhibited infection dissemination. Unexpectedly, STING activation also supported mutant DENV replication in infected cells through STING-induced autophagy. Our findings thus show that DENV NS2B has multi-faceted role in controlling DENV replication rate and immune evasion and suggest that the dual role of STING in supporting virus replication within infected cells but inhibiting infection dissemination could be particularly advantageous for live attenuated vaccine development.
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spelling pubmed-97487852022-12-16 A fast-growing dengue virus mutant reveals a dual role of STING in response to infection Ng, Wy Ching Kwek, Swee Sen Sun, Bo Yousefi, Meisam Ong, Eugenia Z. Tan, Hwee Cheng Puschnik, Andreas S. Chan, Kuan Rong Ooi, Yaw Shin Ooi, Eng Eong Open Biol Research The four dengue viruses (DENVs) have evolved multiple mechanisms to ensure its survival. Among these mechanisms is the ability to regulate its replication rate, which may contribute to avoiding premature immune activation that limit infection dissemination: DENVs associated with dengue epidemics have shown slower replication rate than pre-epidemic strains. Correspondingly, wild-type DENVs replicate more slowly than their clinically attenuated derivatives. To understand how DENVs ‘make haste slowly’, we generated and screened for DENV2 mutants with accelerated replication that also induced high type-I interferon (IFN) expression in infected cells. We chanced upon a single NS2B-I114T amino acid substitution, in an otherwise highly conserved amino acid residue. Accelerated DENV2 replication damaged host DNA as mutant infection was dependent on host DNA damage repair factors, namely RAD21, EID3 and NEK5. DNA damage induced cGAS/STING signalling and activated early type-I IFN response that inhibited infection dissemination. Unexpectedly, STING activation also supported mutant DENV replication in infected cells through STING-induced autophagy. Our findings thus show that DENV NS2B has multi-faceted role in controlling DENV replication rate and immune evasion and suggest that the dual role of STING in supporting virus replication within infected cells but inhibiting infection dissemination could be particularly advantageous for live attenuated vaccine development. The Royal Society 2022-12-14 /pmc/articles/PMC9748785/ /pubmed/36514984 http://dx.doi.org/10.1098/rsob.220227 Text en © 2022 The Authors. https://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research
Ng, Wy Ching
Kwek, Swee Sen
Sun, Bo
Yousefi, Meisam
Ong, Eugenia Z.
Tan, Hwee Cheng
Puschnik, Andreas S.
Chan, Kuan Rong
Ooi, Yaw Shin
Ooi, Eng Eong
A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title_full A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title_fullStr A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title_full_unstemmed A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title_short A fast-growing dengue virus mutant reveals a dual role of STING in response to infection
title_sort fast-growing dengue virus mutant reveals a dual role of sting in response to infection
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748785/
https://www.ncbi.nlm.nih.gov/pubmed/36514984
http://dx.doi.org/10.1098/rsob.220227
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