ABSTRACT
The association of Zika virus (ZIKV) infection with a congenital malformation in fetuses, neurological, and other systemic complications in adults have brought significant global health emergency. ZIKV targets nerve cells in the brain and causes cell death, such as pyroptosis, leading to neuroinflammation. Here we described a novel mechanism of pyroptosis caused by ZIKV protease. We found that ZIKV protease directly cleaved the GSDMD into N-terminal fragment (1-249) leading to pyroptosis in a caspase-independent manner, suggesting a direct mechanism of ZIKV-induced cell death and subsequent inflammation. Our findings might shed new light to explore the pathogenesis of ZIKV infections where ZIKV protease might be a suitable target for the development of antiviral agents.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Peptide Hydrolases/metabolism , Phosphate-Binding Proteins/metabolism , Pyroptosis/physiology , Viral Proteins/metabolism , Zika Virus/enzymology , Zika Virus/pathogenicity , Binding Sites , Caspases/metabolism , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Models, Biological , Neurons/metabolism , Neurons/pathology , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Phosphate-Binding Proteins/chemistry , Proteolysis , Substrate Specificity , Zika Virus Infection/etiology , Zika Virus Infection/metabolism , Zika Virus Infection/pathologyABSTRACT
The pandemic of COVID-19 is spreading unchecked due to the lack of effective antiviral measures. Silver nanoparticles (AgNP) have been studied to possess antiviral properties and are presumed to inhibit SARS-CoV-2. Due to the need for an effective agent against SARS-CoV-2, we evaluated the antiviral effect of AgNPs. We evaluated a plethora of AgNPs of different sizes and concentration and observed that particles of diameter around 10 nm were effective in inhibiting extracellular SARS-CoV-2 at concentrations ranging between 1 and 10 ppm while cytotoxic effect was observed at concentrations of 20 ppm and above. Luciferase-based pseudovirus entry assay revealed that AgNPs potently inhibited viral entry step via disrupting viral integrity. These results indicate that AgNPs are highly potent microbicides against SARS-CoV-2 but should be used with caution due to their cytotoxic effects and their potential to derange environmental ecosystems when improperly disposed.
Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Metal Nanoparticles/administration & dosage , Pneumonia, Viral/drug therapy , Silver/administration & dosage , Animals , Antiviral Agents/toxicity , Betacoronavirus/physiology , COVID-19 , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Dose-Response Relationship, Drug , Humans , Metal Nanoparticles/toxicity , Metal Nanoparticles/ultrastructure , Pandemics , Particle Size , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Silver/toxicity , Vero Cells , Virus Internalization/drug effectsABSTRACT
SynNotch receptor technology is a versatile tool that uses the regulatory notch core portion with an extracellular scFv and an intracellular transcription factor that enables to program customized input and output functions in mammalian cells. In this study, we designed a novel synNotch receptor comprising scFv against HBs antigen linked with an intracellular artificial transcription factor and exploited it for viral sensing and cellular immunotherapy. The synNotch receptor expressing cells sensed HBV particles and membrane-bound HBs antigens and responded by expressing reporter molecules, secNL or GFP. We also programmed these cells to dispense antiviral responses such as type I interferon and anti-HBV neutralizing mouse-human chimeric antibodies. Our data reveal that synNotch receptor signaling works for membrane-bound ligands such as enveloped viral particles and proteins borne on liposomal vesicles. This study establishes the concepts of "engineered immunity" where the synNotch platform is utilized for cellular immunotherapy against viral infections.
