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A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses
Journal article   Open access   Peer reviewed

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, …
mBio, v 8(3)
02 May 2017
DOI: https://doi.org/10.1128/mBio.00452-17
PMID: 28465426
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/mbio.00452-17View
Published, Version of Record (VoR) Open
url
https://doi.org/10.1128/mBio.00452-17View
Published, Version of Record (VoR) Open

Abstract

Adaptor Proteins, Vesicular Transport - agonists Adaptor Proteins, Vesicular Transport - metabolism Antiviral Agents - chemistry Antiviral Agents - isolation & purification Antiviral Agents - pharmacology Benzopyrans - chemistry Benzopyrans - isolation & purification Benzopyrans - pharmacology Cell Line Chikungunya Fever - drug therapy Chikungunya virus - drug effects Chikungunya virus - physiology Cytokines - biosynthesis Dengue - drug therapy Dengue Virus - drug effects Dengue Virus - metabolism Dengue Virus - physiology DNA Replication - drug effects Drug Discovery Gene Editing Host-Pathogen Interactions Humans Immune Evasion Immunity, Innate - drug effects Interferon Regulatory Factor-3 - genetics Interferon Regulatory Factor-3 - metabolism Interferon Type I - drug effects Interferon Type I - metabolism Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - immunology Thiadiazoles - chemistry Thiadiazoles - isolation & purification Thiadiazoles - pharmacology Virus Replication Zika Virus - drug effects Zika Virus - physiology
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- ]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. 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.

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38 citations in Web of Science
34 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Microbiology
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