Biology subjects

Meng, X.-J.

Publications and source records attributed to Meng, X.-J..

2 recordsLinked to original sources

bioRxiv2025

Auranofin Inhibits Hepatitis E Virus Replication Via Reactive Oxygen Species

Hepatitis E virus (HEV) causes roughly 20 million yearly global infections, and is associated with chronic hepatitis, neurological sequelae and pregnancy-related adverse outcomes that require antiviral therapeutic intervention. While there are currently no approved HEV-specific therapeutics, ribavirin and pegylated interferon, prescribed off-label, are the current standard of care. However, ribavirin resistance and toxicity highlight the unmet clinical need to identify safer, HEV-specific antivirals. Auranofin, an FDA-approved anti-rheumatic drug, displays antiviral activity against several viruses. Therefore, we investigated auranofins potential as an antiviral and its mechanism of action against HEV. We demonstrated that auranofin displays dose-dependent antiviral activity against two genotypes of HEV that cause a significant proportion of human disease, as well as against a ribavirin treatment failure-associated mutant. Because auranofin is known to increase reactive oxygen species (ROS), we investigated the antiviral mechanism of action via treatment with ROS inhibitors. ROS inhibitors reversed auranofin-mediated ROS promotion and antiviral activity, suggesting the observed antiviral effects are mediated by ROS. Furthermore, treatment with a different ROS promotor, D-amino acid oxidase (DAAO), also displays antiviral activity against HEV, which was also reversed by treatment with a ROS inhibitor, suggesting that ROS accumulation alone is antiviral. We also demonstrated that combined treatment with auranofin and ribavirin exhibits synergistic antiviral activity in vitro, which supports repurposing auranofin as an antiviral against HEV, potentially in combination with ribavirin. Overall, this study has important implications in repurposing auranofin as an antiviral against HEV and in delineating the mechanism of action against HEV via ROS. ImportanceHepatitis E virus (HEV) lacks approved antiviral therapies, and off-label treatments are limited by toxicity and emerging resistance. This study identifies the FDA-approved drug auranofin as an effective in vitro inhibitor of HEV, including two globally relevant human-associated genotypes and a ribavirin treatment failure-associated mutant. Auranofins activity highlights the therapeutic potential of host-targeting antivirals, particularly those that promote the generation of reactive oxygen species, in treating HEV infection. These findings support further in vivo investigations of auranofin as a treatment for HEV and suggest that modulating host redox pathways by promoting reactive oxygen species may represent a promising strategy for broad-spectrum antiviral development.

microbiology↗

bioRxiv2021

Killed whole genome-reduced bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model

As the coronavirus disease 2019 (COVID-19) pandemic rages on, it is important to explore new evolution-resistant vaccine antigens and new vaccine platforms that can produce readily scalable, inexpensive vaccines with easier storage and transport. We report here a synthetic biology-based vaccine platform that employs an expression vector with an inducible Gram-negative autotransporter to express vaccine antigens on surface of genome-reduced bacteria to enhance interaction of vaccine antigen with immune system. As a proof of principle, we utilized genome-reduced E. coli to express SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV) fusion peptide (FP) on the cell surface, and evaluated their use as a killed whole cell vaccine. The FP sequence is highly conserved across coronaviruses; the 6 FP core amino acid residues along with the 4 adjacent residues upstream and the 3 residues downstream the core are identical between SARS-CoV-2 and PEDV. We tested the efficacy of PEDV FP and SARS-CoV-2 FP vaccines in a PEDV challenge pig model. We demonstrated that both vaccines induced potent anamnestic responses upon virus challenge, potentiated IFN-{gamma} responses, reduced viral RNA loads in jejunum tissue, and provided significant protection against clinical disease. However, neither vaccines elicited sterilizing immunity. Since SARS-CoV-2 FP and PEDV FP vaccines provided similar clinical protection, the coronavirus FP could be a target for a broadly-protective vaccine using any platform. Importantly, the genome-reduced bacterial surface-expressed vaccine platform, when using a vaccine appropriate bacterial vector, has potential utility as an inexpensive, readily manufactured, and rapid vaccine platform for other pathogens. Significance StatementWe report a new vaccine platform to express vaccine antigens on surface of genome-reduced bacteria to enhance vaccine immunogenicity. We demonstrated the utility of this vaccine platform by expressing the highly conserved fusion peptide (FP) of SARS-CoV-2 and porcine epidemic diarrhea virus on the surface of E.coli to produce killed whole cell bacterial vaccines. The vaccine primes a potent anamnestic response, potentiates IFN-{gamma} responses, and provides significant protection in pigs against disease following virus challenge. The FP could be a target for a broadly-protective coronavirus vaccine since a Betacoronavirus SARS-CoV-2 FP vaccine provided cross-protection against Alphacoronavirus PEDV. When using a vaccine appropriate bacteria vector, this inexpensive new vaccine platform offers the potential for use in developing countries.

microbiology↗