Biology subjects

Winther, G.

Publications and source records attributed to Winther, G..

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↗

bioRxiv2026

Thymic Treg-derived T follicular regulatory cells prevent catastrophic humoral autoimmunity in response to TLR7-driven inflammation

T follicular regulatory cells (TFR) are a follicle-resident subset of regulatory T cells (TREG) that limit germinal center (GC) responses and enforce humoral tolerance. Although TFR are known to focus antibody responses to foreign antigens, how GC-specific regulation is maintained during inflammation remains unclear. Here, TLR7-driven inflammation unmasked a critical, non-redundant role for TFR in preserving immune tolerance. Selective loss of TFR caused severe autoimmunity and increased mortality, driven by inflammation-induced expansion of autoreactive B and T cell clones and epitope spreading. Autoreactivity resolved upon cessation of inflammation in TFR-sucicient mice but persisted in their absence. Mechanistically, TFR limited the establishment and expansion of spontaneous GCs in response to inflammation, and responding TFR displayed transcriptional, phenotypic, and clonal features of thymic TREG. This suggests that whereas TFH upregulate FoxP3 to shut down end-stage GCs, it is thymic TREG-derived TFR that safeguard GC integrity under inflammatory stress to prevent lethal autoimmunity.

immunology↗

bioRxiv2018

The behavioral and neurobiological effects of reduced Brd1 expression in mice are sex-biased and implicate gender dependent dysregulation of nuclear receptor mediated signaling in mental disorders

The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/- mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/- mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/- mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/- mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.

neuroscience↗