Biology subjects

Vaegter, C.

Publications and source records attributed to Vaegter, C..

3 recordsLinked to original sources

bioRxiv2026

Distinct roles for DNA- and RNA-sensing immune pathways in control of genital HSV-2 infection and restriction of neuroinvasion

Early control of viral infection is thought to rely on pattern-recognition receptors (PRRs) that induce interferons (IFNs) and leukocyte recruitment, but how distinct PRRs coordinate mucosal antiviral defense remains unclear. We show that both the DNA-sensing cGAS-STING pathway and the RNA-sensing RLR-MAVS pathway are required for protection upon genital herpes simplex virus type 2 (HSV-2) infection. cGAS deficiency increased infection-induced pathology in both epithelial and submucosal compartments, whereas MAVS deficiency primarily affected the epithelium. Spatial proteomics and regional transcriptomics revealed that cGAS was essential for early epithelial TBK1 activation, expression of IFN-stimulated genes and recruitment and activation of myeloid and lymphoid cells to the epithelium. While MAVS was essential for full TBK1 activation it had limited impact on the induced IFN response. However, MAVS sustained basal epithelial expression of the antiviral factors IFITM1 and 3, which exert antiviral activity against HSV-2. Notably, cGAS deficiency impaired submucosal IFN responses and enabled viral spread into this tissue, enabling infection of intervening neurons and dissemination to the central nervous system. These findings define coordinated, compartment-specific innate defense against infections.

immunology↗

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2024

Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of extra-nigral Synucleinopathy.

A pathological role of alpha-Synuclein (aSyn) aggregation in the central nervous system (CNS) is a recognized feature in Parkinson disease (PD) and related neurodegenerative conditions termed synucleinopathies. In order to characterize the cellular response in CNS to incipient and advanced aSyn pathology, we applied spatial transcriptomics on brain sections derived from a transgenic mouse model (M83+/+ line, Prnp-SNCA*A53T) in which aSyn aggregation was induced in a prion-like fashion through hindlimb intramuscular delivery of pre-formed fibrillar (PFF) murine aSyn. Our spatially-resolved transcriptomics (ST) data point to unique perturbations in brain energy metabolism during the progression of aSyn pathology, such that the early stage of aSyn aggregate pathology activates molecular pathways controlling metabolic flux through glycolysis, oxidative phosphorylation and fatty acid metabolism. In contrast, the ST data indicate a profound decline in mitochondrial metabolism in the brains of symptomatic animals with advanced aSyn pathology. The latter stage was also associated with drastic reduction in mRNA translation machinery, along with aberrant expression of molecular drivers involved in RNA splicing and inflammatory response. Intriguingly, our ST data also point to perturbed regulation of circadian rhythm, was corroborated by increased immunodetection of CREB-binding protein (a modulator of core clock machinery) in the brains of symptomatic animals, and transcriptional upregulation of CREBBP in 4 independent PD microarray datasets. Collectively, we anticipate that our findings offer novel opportunities in knowledge translation for mechanism-based drug discovery and biomarkers in neurodegenerative synucleinopathies.

neuroscience↗