Biology subjects

Bonney, S.

Publications and source records attributed to Bonney, S..

5 recordsLinked to original sources

bioRxiv2026

Chemogenetic Pericyte Activation Reveals Broad Contractile Ability and Limbic Vulnerability to Capillary Flow Deficits

Capillary pericytes contact most of the brains microvasculature. Yet, their influence on blood flow remains incompletely understood both locally in capillary networks and across brain regions. Here, we sparsely expressed the chemogenetic actuator Gq-DREADD in mouse brain pericytes to stochastically probe their contractility and influence on tissue perfusion and oxygenation. Chemogenetic stimulation induced robust contraction of pericytes over minutes, including those with thin processes on capillary segments proximal to venules, indicating control of vascular tone across the entire capillary bed. Pericyte contraction combined circumferential compression with longitudinal tension applied through thin processes, resulting in vasoconstriction and hypoperfusion. Histology revealed hypoxic microdomains induced by sparse pericyte contraction across the brain, and enriched hypoxia in limbic structures including the amygdala and hippocampus. These microscale perfusion deficits were undetectable by arterial spin labeling MRI. Our findings reveal the in vivo mechanics of pericyte contraction and identify limbic system vulnerability to capillary flow impairment.

neuroscience↗

bioRxiv2022

Formation and function of the meninges arachnoid barrier around the developing brain

Barriers at the level of the brain endothelium, choroid plexus, and meninges strictly regulate movement of molecules and cells into and out of the central nervous system (CNS). In contrast to the blood-brain barrier and choroid plexus epithelial barrier, developmental timing and function of the meningeal arachnoid barrier, a layer of epithelial-like cells connected by tight and adherens junctions, is largely unknown. To begin to address this, we mined our E14.5 mouse single cell transcriptomic (scRNA-seq) meningeal fibroblast data set and identified the repression of Wnt-{beta}-catenin signaling as a key mechanism underlying the specification of epithelial-like arachnoid barrier cells from Collagen 1+ and Crabp2+ mesenchymal meningeal precursors. We show that elevating Wnt-{beta}-catenin signaling in prenatal meningeal mesenchymal cells prevented the development of arachnoid barrier cells. In the absence of dorsal arachnoid barrier cells, the prenatal meninges and brain are penetrable to biocytin-TMR and Streptococcus agalactiae (Group B Streptococcus, GBS), the leading pathogen known to drive life-threatening neonatal meningitis. We show that a layer of Claudin 11 (tight junction) and E-cadherin (adherens junction) expressing arachnoid barrier cells appear around the mouse brain from E13-E15 and the emergence of a functional barrier by E17 coincides with junctional localization of Claudin 11. Postnatal growth of the arachnoid barrier is marked initially by proliferation and later re-organization of junctional domains. This work provides fundamental knowledge on development and prenatal function of a meningeal arachnoid barrier, and novel tools for future studies on regional functions of this CNS barrier in the meninges.

developmental biology↗

bioRxiv2022

Multicomponent Pseudomonas aeruginosa vaccines eliciting Th17 cells and functional antibody responses confer enhanced protection against experimental acute pneumonia in mice

The Gram-negative pathogen Pseudomonas aeruginosa is a common cause of pneumonia in hospitalized patients. Its increasing antibiotic resistance and widespread occurrence present a pressing need for vaccines. We previously showed that a P. aeruginosa type III secretion system protein, PopB elicits a strong Th17 response in mice after intranasal (IN) immunization and confers antibody-independent protection against pneumonia in mice. In the current study, we evaluated the immunogenicity and protective efficacy in mice of the combination of PopB (purified with its chaperone protein PcrH) and OprF/I, an outer membrane hybrid fusion protein, compared to immunization with the proteins individually either by the intranasal (IN) or subcutaneous (SC) routes. Our results show that after vaccination, a Th17 recall response from splenocytes was detected only in mice vaccinated with PopB/PcrH, either alone or in combination with OprF/I. Mice that were immunized with the combination of PopB/PcrH and OprF/I had enhanced protection in an acute lethal P. aeruginosa pneumonia model, regardless of vaccine route, compared to the mice vaccinated the with either alone or adjuvant control. Immunization generated IgG titers against the vaccine proteins and whole P. aeruginosa cells. Interestingly, none of these antisera had opsonophagocytic killing activity, but antisera from mice immunized with vaccines containing OprF/I had the ability to block IFN-{gamma} binding to OprF/I, a known virulence mechanism. Hence, vaccines combining PopB/PcrH with OprF/I that elicit functional antibodies lead to a broadly and potently protective vaccine against P. aeruginosa pulmonary infections.

immunology↗

bioRxiv2019

Nature based measures reverse catchment biodiversity loss and increase freshwater resilience in an agricultural landscape

This is the first study that describes the effect of adding mitigation measures on the freshwater biodiversity of all waterbody types in agricultural catchments. We measured alpha (site) and gamma (catchment) richness annually over a nine-year period in all the streams, ponds and ditches in three upper-catchments in the English lowlands, and investigated whether freshwater plant biodiversity could be increased by adding: (i) multi-functional ecosystem services measures to intercept pollutants, store water and promote biodiversity, and, (ii) biodiversity-only protection measures. In the absence of measures, all catchments saw a decline in macrophyte richness during the survey (mean species loss of 1% pa, rare species loss of 2% pa). Ponds were a key habitat with a disproportionate influence on catchment trends. Five years after introducing measures, natural colonisation of ecosystem services waterbodies (dammed streams and ditches, runoff ponds, flood storage ponds) largely cancelled-out the background loss of plant species but, importantly, did not restore the loss of rare plants. Adding clean water ponds as a biodiversity-only enhancement measure brought substantial benefits: increasing total-catchment richness by 26%, and the number of rare plant species by 181%. Populations of spatially restricted species also increased. Adding stream debris-dams as a biodiversity measure did not affect plant richness or rarity. The findings suggest that ecosystem services measures could bring some biodiversity benefits to agricultural catchments. However, creating clean-water ponds specifically targeted for biodiversity could hold considerable potential as a tool to help stem, and even reverse, ongoing declines in freshwater plant biodiversity across farming landscapes.

ecology↗

bioRxiv2019

A cellular atlas of the developing meninges reveals meningeal fibroblast diversity and function

The meninges, a multilayered structure that encases the CNS, is composed mostly of fibroblasts, along with vascular and immune cells. Meningeal fibroblasts are a vital source of signals that control neuronal migration and neurogenesis yet strikingly little is known about their development. We used single cell RNA sequencing to generate a cellular atlas of embryonic meningeal fibroblasts in control and Foxc1-KO mice in which severe CNS defects arise from failed meningeal fibroblast development. We report unique transcriptional signatures for dura, arachnoid and pial fibroblasts and identify S100a6 as the first unique marker of the pial layer. We describe a new meningeal fibroblast subtype marked by {micro}-Crystallin expression and show these cell types and markers are conserved in human fetal meninges. Our analysis demonstrates layer specific production of extracellular matrix components, transporter expression, and synthesis of secreted factors. Lastly, the cellular atlas of Foxc1-KO meninges provides insight into their severe phenotype, confirming a massive loss in arachnoid and dura fibroblasts and Foxc1-KO pial fibroblasts are so altered that they cluster as a different cell type based on gene expression. These studies provide an unprecedented view of meningeal fibroblast development, highlighting unexpected fibroblast diversity and function, while providing mechanistic insights into the meninges role in CNS development.

neuroscience↗