$A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses$
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A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively bl...

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Autores principales:	Kara M. Pryke, Jinu Abraham, Tina M. Sali, Bryan J. Gall, Iris Archer, Andrew Liu, Shelly Bambina, Jason Baird, Michael Gough, Marita Chakhtoura, Elias K. Haddad, Ilsa T. Kirby, Aaron Nilsen, Daniel N. Streblow, Alec J. Hirsch, Jessica L. Smith, Victor R. DeFilippis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	antiviral agents emerging virus innate immunity interferons Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/09f2dc17e4774d63a4c91dc285882276
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spelling	oai:doaj.org-article:09f2dc17e4774d63a4c91dc2858822762021-11-15T15:51:29ZA Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses10.1128/mBio.00452-172150-7511https://doaj.org/article/09f2dc17e4774d63a4c91dc2858822762017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00452-17https://doaj.org/toc/2150-7511ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. IMPORTANCE The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.Kara M. PrykeJinu AbrahamTina M. SaliBryan J. GallIris ArcherAndrew LiuShelly BambinaJason BairdMichael GoughMarita ChakhtouraElias K. HaddadIlsa T. KirbyAaron NilsenDaniel N. StreblowAlec J. HirschJessica L. SmithVictor R. DeFilippisAmerican Society for Microbiologyarticleantiviral agentsemerging virusinnate immunityinterferonsMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	antiviral agents emerging virus innate immunity interferons Microbiology QR1-502
spellingShingle	antiviral agents emerging virus innate immunity interferons Microbiology QR1-502 Kara M. Pryke Jinu Abraham Tina M. Sali Bryan J. Gall Iris Archer Andrew Liu Shelly Bambina Jason Baird Michael Gough Marita Chakhtoura Elias K. Haddad Ilsa T. Kirby Aaron Nilsen Daniel N. Streblow Alec J. Hirsch Jessica L. Smith Victor R. DeFilippis A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
description	ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. IMPORTANCE The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.
format	article
author	Kara M. Pryke Jinu Abraham Tina M. Sali Bryan J. Gall Iris Archer Andrew Liu Shelly Bambina Jason Baird Michael Gough Marita Chakhtoura Elias K. Haddad Ilsa T. Kirby Aaron Nilsen Daniel N. Streblow Alec J. Hirsch Jessica L. Smith Victor R. DeFilippis
author_facet	Kara M. Pryke Jinu Abraham Tina M. Sali Bryan J. Gall Iris Archer Andrew Liu Shelly Bambina Jason Baird Michael Gough Marita Chakhtoura Elias K. Haddad Ilsa T. Kirby Aaron Nilsen Daniel N. Streblow Alec J. Hirsch Jessica L. Smith Victor R. DeFilippis
author_sort	Kara M. Pryke
title	A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
title_short	A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
title_full	A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
title_fullStr	A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
title_full_unstemmed	A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
title_sort	novel agonist of the trif pathway induces a cellular state refractory to replication of zika, chikungunya, and dengue viruses
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/09f2dc17e4774d63a4c91dc285882276
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A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

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