ABSTRACT
Flaviviruses including Zika, Dengue and Hepatitis C virus cause debilitating diseases in humans, and the former are emerging as global health concerns with no antiviral treatments. We investigated Sophora Flavecens, used in Chinese medicine, as a source for antiviral compounds. We isolated Sophoraflavenone G and found that it inhibited Hepatitis C replication, but not Sendai or Vesicular Stomatitis Virus. Pre- and post-infection treatments demonstrated anti-flaviviral activity against Dengue and Zika virus, via viral RNA polymerase inhibition. These data suggest that Sophoraflavenone G represents a promising candidate regarding anti-Flaviviridae research.
Subject(s)
Antiviral Agents/pharmacology , Dengue Virus/drug effects , Flavanones/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Sophora/chemistry , Zika Virus/drug effects , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Cell Line , Dengue/drug therapy , Dengue Virus/enzymology , Dengue Virus/physiology , Drug Discovery , Flavanones/chemistry , Flavanones/isolation & purification , Flaviviridae/drug effects , Hepacivirus/drug effects , Humans , Plant Roots/chemistry , Virus Replication/drug effects , Zika Virus/enzymology , Zika Virus/physiology , Zika Virus Infection/drug therapyABSTRACT
Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the antioxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models. Chemoresistant A549 lung cancer cells that display constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulated viral replication in cancer cells and disrupted the type I IFN response via increased autophagy. This study reveals a previously unappreciated role for Nrf2 in the regulation of autophagy and the innate antiviral response that complements the therapeutic potential of VSV-directed oncolysis against multiple types of OV-resistant or chemoresistant cancer.
Subject(s)
Autophagy , NF-E2-Related Factor 2/metabolism , Oncolytic Viruses/physiology , Signal Transduction , Vesicular Stomatitis/metabolism , Vesicular Stomatitis/virology , Vesicular stomatitis Indiana virus/physiology , Animals , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Autophagy/drug effects , Cell Line , Combined Modality Therapy , Disease Models, Animal , Host-Pathogen Interactions/immunology , Humans , Immunity/drug effects , Immunity, Innate/drug effects , Isothiocyanates/pharmacology , Mice , Mice, Knockout , NF-E2-Related Factor 2/genetics , Neoplasms/metabolism , Neoplasms/mortality , Neoplasms/pathology , Neoplasms/therapy , Oncolytic Virotherapy , Sequence Deletion , Signal Transduction/drug effects , Sulfoxides , Vesicular Stomatitis/immunology , Vesicular stomatitis Indiana virus/drug effects , Viral Matrix Proteins/genetics , Virus Replication/drug effectsABSTRACT
UNLABELLED: STING has emerged in recent years as a key player in orchestrating innate immune responses to cytosolic DNA and RNA derived from pathogens. However, the regulation of STING still remains poorly defined. In the present study, we investigated the mechanism of the regulation of STING expression in relation to the RIG-I pathway. Our data show that signaling through RIG-I induces STING expression at both the transcriptional and protein levels in various cell types. STING induction by the RIG-I agonist 5'triphosphorylated RNA (5'pppRNA) was recognized to be a delayed event resulting from an autocrine/paracrine mechanism. Indeed, cotreatment with tumor necrosis factor alpha and type I/II interferon was found to have a synergistic effect on the regulation of STING expression and could be potently decreased by impairing NF-κB and/or STAT1/2 signaling. STING induction significantly contributed to sustainment of the immune signaling cascade following 5'pppRNA treatment. Physiologically, this cross talk between the RNA- and DNA-sensing pathways allowed 5'pppRNA to efficiently block infection by herpes simplex virus 1 (HSV-1) both in vitro and in vivo in a STING-dependent fashion. These observations demonstrate that STING induction by RIG-I signaling through the NF-κB and STAT1/2 cascades is essential for RIG-I agonist-mediated HSV-1 restriction. IMPORTANCE: The innate immune system represents the first line of defense against invading pathogens. The dysregulation of this system can result in failure to combat pathogens, inflammation, and autoimmune diseases. Thus, precise regulation at each level of the innate immune system is crucial. Recently, a number of studies have established STING to be a central molecule in the innate immune response to cytosolic DNA and RNA derived from pathogens. Here, we describe the regulation of STING via RIG-I-mediated innate immune sensing. We found that STING is synergistically induced via proinflammatory and antiviral cytokine cascades. In addition, we show that in vivo protection against herpes simplex virus 1 (HSV-1) by a RIG-I agonist required STING. Our study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING.
