A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses

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 Streblow, Alec Hirsch, Jessica L. Smith, Victor De Filippis

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere00452-17
JournalmBio
Volume8
Issue number3
DOIs
StatePublished - May 1 2017

Fingerprint

Chikungunya virus
Dengue Virus
Interferon Type I
Adaptive Immunity
Interferon Regulatory Factor-3
Viruses
Interferons
Antiviral Agents
Vertebrates
Flavivirus
Pyrroles
Latin America
Zoonoses
Virus Diseases
Growth
Innate Immunity
Disease Outbreaks
Blood Cells
Proteins
Therapeutics

Keywords

  • Antiviral agents
  • Emerging virus
  • Innate immunity
  • Interferons

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Pryke, K. M., Abraham, J., Sali, T. M., Gall, B. J., Archer, I., Liu, A., ... De Filippis, V. (2017). A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses. mBio, 8(3), [e00452-17]. https://doi.org/10.1128/mBio.00452-17

A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses. / Pryke, Kara M.; Abraham, Jinu; Sali, Tina M.; Gall, Bryan J.; Archer, Iris; Liu, Andrew; Bambina, Shelly; Baird, Jason; Gough, Michael; Chakhtoura, Marita; Haddad, Elias K.; Kirby, Ilsa T.; Nilsen, Aaron; Streblow, Daniel; Hirsch, Alec; Smith, Jessica L.; De Filippis, Victor.

In: mBio, Vol. 8, No. 3, e00452-17, 01.05.2017.

Research output: Contribution to journalArticle

Pryke, KM, Abraham, J, Sali, TM, Gall, BJ, Archer, I, Liu, A, Bambina, S, Baird, J, Gough, M, Chakhtoura, M, Haddad, EK, Kirby, IT, Nilsen, A, Streblow, D, Hirsch, A, Smith, JL & De Filippis, V 2017, 'A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses', mBio, vol. 8, no. 3, e00452-17. https://doi.org/10.1128/mBio.00452-17
Pryke, Kara M. ; Abraham, Jinu ; Sali, Tina M. ; Gall, Bryan J. ; Archer, Iris ; Liu, Andrew ; Bambina, Shelly ; Baird, Jason ; Gough, Michael ; Chakhtoura, Marita ; Haddad, Elias K. ; Kirby, Ilsa T. ; Nilsen, Aaron ; Streblow, Daniel ; Hirsch, Alec ; Smith, Jessica L. ; De Filippis, Victor. / A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses. In: mBio. 2017 ; Vol. 8, No. 3.
@article{bd523415d2424f9993a34a6ef48efe89,
title = "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 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.",
keywords = "Antiviral agents, Emerging virus, Innate immunity, Interferons",
author = "Pryke, {Kara M.} and Jinu Abraham and Sali, {Tina M.} and Gall, {Bryan J.} and Iris Archer and Andrew Liu and Shelly Bambina and Jason Baird and Michael Gough and Marita Chakhtoura and Haddad, {Elias K.} and Kirby, {Ilsa T.} and Aaron Nilsen and Daniel Streblow and Alec Hirsch and Smith, {Jessica L.} and {De Filippis}, Victor",
year = "2017",
month = "5",
day = "1",
doi = "10.1128/mBio.00452-17",
language = "English (US)",
volume = "8",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "3",

}

TY - JOUR

T1 - A novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses

AU - Pryke, Kara M.

AU - Abraham, Jinu

AU - Sali, Tina M.

AU - Gall, Bryan J.

AU - Archer, Iris

AU - Liu, Andrew

AU - Bambina, Shelly

AU - Baird, Jason

AU - Gough, Michael

AU - Chakhtoura, Marita

AU - Haddad, Elias K.

AU - Kirby, Ilsa T.

AU - Nilsen, Aaron

AU - Streblow, Daniel

AU - Hirsch, Alec

AU - Smith, Jessica L.

AU - De Filippis, Victor

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Antiviral agents

KW - Emerging virus

KW - Innate immunity

KW - Interferons

UR - http://www.scopus.com/inward/record.url?scp=85022336573&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85022336573&partnerID=8YFLogxK

U2 - 10.1128/mBio.00452-17

DO - 10.1128/mBio.00452-17

M3 - Article

C2 - 28465426

AN - SCOPUS:85022336573

VL - 8

JO - mBio

JF - mBio

SN - 2161-2129

IS - 3

M1 - e00452-17

ER -