Biology subjects

Griffin, D. E.

Publications and source records attributed to Griffin, D. E..

4 recordsLinked to original sources

bioRxiv2026

Encephalitic Alphavirus Infection Induces PARP-1 Hyperactivation Mediated Energy Collapse in Motor Neurons

Motor neurons are highly vulnerable to metabolic stress, yet the mechanisms driving their degeneration during neurotropic alphavirus infections remain unclear. Venezuelan equine encephalitis virus (VEEV) causes motor neuron injury, but the intrinsic pathways underlying this susceptibility are not fully defined. Previous work suggests alphavirus-infected motor neurons may die through caspase-independent mechanisms. Here, we show that VEEV infection induces sustained activation of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), leading to depletion of NAD+ and ATP in murine NSC34 motor neuron-like cells and human iPSC-derived motor neurons. These metabolic changes precede mitochondrial depolarization and cell death. Pharmacological inhibition or genetic reduction of PARP-1 partially restores NAD+ and ATP and improves cell survival, indicating that PARP-1 hyperactivation directly contributes to energetic collapse and intrinsic motor neuron death. These results identify PARP-1 as a key driver of energy failure during VEEV infection and a potential target to limit neuronal injury in neurotropic viral infections.

microbiology↗

bioRxiv2025

Acute induction of IFNα is responsible for the attenuation of the live measles vaccine

The live-attenuated measles vaccine (LAMV) protects against measles in a safe, efficacious and durable manner. However, the mechanism by which LAMV is attenuated is not well understood, contributing to the increased vaccine hesitancy that has caused a worldwide resurgence of measles. Here, we provide a molecular model of attenuation that implicates increased host innate immune responses and increased LAMV susceptibility to those responses. Our study leverages both in vitro and in vivo models of infection to find that acute induction of innate immunity in immune cells is the critical determinant of LAMV attenuation. We show that LAMV, in contrast to pathogenic wild type measles virus (MeV), causes a strong IFN response in primary human peripheral blood mononuclear cells, which restricts viral replication and spread in a post-entry manner. LAMV can enter, transcribe viral mRNA and translate viral proteins in immune cells, but is not able to form infectious particles and spread from cell to cell. Specifically, we find that mutations conserved across LAMV strains in the P/V/C and H genes are responsible for the induction of IFN and the restriction of infectious virus production. In PBMC cultures and in rhesus macaques, LAMV infection also results in the acute induction of proinflammatory cytokines that likely play a role in the immunogenicity of the vaccine. Overall, our study provides a virological and immunological framework for LAMV attenuation which can be leveraged in repurposing the LAMV backbone and in future vaccine design.

microbiology↗

bioRxiv2024

Decreasing ZAP Poly(ADP-ribose) Binding Enhances Antiviral Activity Against Alphaviruses

Zinc finger antiviral protein (ZAP), also known as PARP13, is an antiviral factor effective against several virus families. ZAP contains three major protein domains: N-terminal zinc fingers, central WWE domains, and a C-terminal inactive ADP-ribosyltransferase domain, which is present only in the longer isoform ZAPL. While both the zinc finger and ADP-ribosyltransferase domains inhibit viral replication, the role of the WWE domains remains unclear. WWE domains bind poly(ADP-ribose) (PAR). In this study, we focus on ZAPS, the shorter isoform comprised of the minimal unit that confers antiviral activity and lacking the ADP-ribosyltransferase domain, to investigate how PAR-binding contributes to antiviral defense against alphaviruses. We identified the Y659 residue on the second WWE domain as essential for PAR-binding both in vitro and in cells. When infected with Chikungunya or Sindbis virus, cells with the Y659A mutant of ZAPS had reduced formation of replication complexes, decreased levels of viral genomic and subgenomic transcripts, and fewer infectious virions released compared to cells with the unmutated ZAPS, suggesting enhanced antiviral activity of the PAR-binding mutant. These findings suggest that inhibiting PAR-binding in ZAPS could potentiate host antiviral functions, offering a novel therapeutic strategy against alphavirus infections.

microbiology↗

bioRxiv2019

Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

Formation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1. We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADP-ribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions.

cell biology↗