Biology subjects

Full, F.

Publications and source records attributed to Full, F..

5 recordsLinked to original sources

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2024

Poxviruses induce a nuclear environment in the cytoplasm to promote viral replication

The family Orthopoxviridae comprises several members that can cause disease in humans, including Small-, Cow-, Camel-, and Monkeypoxvirus. In 2022 a global outbreak of the zoonotic monkeypoxvirus started with human- to- human transmission and more than 100 000 global cases in all continents. This outbreak emphasizes the need for more basic research to get a better understanding of poxvirus biology. We characterized the cellular response to poxvirus infection and performed bulk RNA-sequencing of primary human fibroblasts infected with Modified-Vaccinia Ankara Virus (MVA), Vaccinia Virus, Cowpoxvirus, Camelpoxvirus and 4 different Monkeypoxvirus isolates (clade 1-2b) at various time points to compare the transcriptome of infected cells. We could demonstrate that MVA infection leads to a potent activation of innate immune genes that is absent in other samples. Camelpoxvirus infection results in a strong activation of NF-kB signaling 2h post infection whereas all other viruses inhibit NF-kB activation. In addition, we observed transport of cellular proteins like histone H1, lamin A/C, emerin and topoisomerase II A/B from the nucleus into cytoplasmic poxvirus factories. This correlates with drastic structural changes inside the nucleus in electron microscopy, namely formation of nuclear filaments, indicating intensive remodeling of the nuclear architecture. Accordingly, inhibition of topoisomerase using the clinically approved topoisomerase inhibitor epirubicin reduced viral replication of several Mpox strains. We observe a reduction of viral replication by epirubicin in cells of human and mouse species, indicating that the recruitment of TOP2B into viral factories is crucial for MPXV replication.

microbiology↗

bioRxiv2024

DNA virus infections shape transposable elements activity in vitro and in vivo

Transposable elements (TEs) are implicated in a variety of processes including placental and preimplantation development and a variety of human diseases. TEs are known to be activated in the context of some viral infections, but the mechanisms and consequences are not understood. We show strong activation of TEs upon DNA virus infection, in particular the MLT- and THE1-class of LTR-containing retrotransposons as well as a subset of LINE-1-, Alu-elements and HERVs. Mechanistically, two key pathways induce TEs upregulation: inhibition of the KAP1/TRIM28 repressive complex by phosphorylation, and expression of the pioneer transcription factor double-homeobox 4 (DUX4), which is known to be involved in TE-induction during zygotic genome activation in embryonic development. DUX4 is induced by DNA viruses, it binds to TEs upon infection and analysis of genes adjacent to TEs shows pathways that are important for DNA virus infections. Analysis of knockdown, knockout and overexpression data reveal that almost all TEs expressed upon herpesviral infection are regulated by KAP1/TRIM28 and DUX4. Interestingly, analysis of single cell sequencing data from patients with DNA virus-associated cancers showed that in vivo TEs expression strongly correlates with virus infection, indicating a possible role in viral oncogenesis.

genomics↗

bioRxiv2021

Dual signaling via interferon and DNA damage response elicits entrapment by giant PML nuclear bodies

PML nuclear bodies (PML-NBs) are dynamic interchromosomal macromolecular complexes implicated in epigenetic regulation as well as antiviral defense. During herpesvirus infection, PML-NBs induce epigenetic silencing of viral genomes, however, this defense is antagonized by viral regulatory proteins such as IE1 of human cytomegalovirus (HCMV). Here, we show that PML-NBs undergo a drastic rearrangement into highly enlarged PML cages upon infection with IE1-deficient HCMV. Importantly, our results demonstrate that dual signaling by interferon and DNA damage response is required to elicit giant PML-NBs. DNA labeling revealed that invading HCMV genomes are entrapped inside PML-NBs and remain stably associated with PML cages in a transcriptionally repressed state. Intriguingly, by correlative light and transmission electron microscopy (EM), we observed that PML cages also entrap newly assembled viral capsids demonstrating a second defense layer in cells with incomplete first line response. Further characterization by 3D EM showed that hundreds of viral capsids are tightly packed into several layers of fibrous PML. Overall, our data indicate that giant PML-NBs arise via combined interferon and DNA damage signaling which triggers entrapment of both nucleic acids and proteinaceous components. This represents a multilayered defense strategy to act in a cytoprotective manner and to combat viral infections.

microbiology↗

bioRxiv2021

Herpesviral induction of germline transcription factor DUX4 is critical for viral gene expression

DUX4 is a transcription factor and a master regulator of embryonic genome activation (EGA). During early embryogenesis, EGA is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is largely silenced. Activation is likely pathogenic, and in adult muscle cells causes genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). We identified activation of DUX4 expression upon lytic replication of the herpesviruses HSV-1, HCMV, EBV and KSHV, but not of adenoviruses, negative strand RNA viruses or positive strand RNA viruses. We demonstrate by RNA-Seq analysis that DUX4 expression upon herpesviral replication leads to the induction of hundreds of DUX4 target genes including germline-specific retroelements as well as several members of the TRIM, PRAMEF and ZSCAN protein families. Moreover, we show that DUX4 expression is a direct consequence of herpesviral infection. DUX4 can be stimulated by overexpression of HSV-1 immediate early proteins, indicating active induction of EGA genes by herpesviral infection. We further show that DUX4 expression is critical for driving HSV-1 gene expression. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. We hypothesize that herpesviruses induce DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.

microbiology↗