Biology subjects

Baumann, K.

Publications and source records attributed to Baumann, K..

6 recordsLinked to original sources

bioRxiv2026

ASC specks and α-synuclein amplify microglial NLRP3 inflammasome activation and co-localize with Lewy body pathology

Neuroinflammation is a hallmark of several chronic neurodegenerative disorders, including Parkinson's disease (PD) and other synucleinopathies, and is closely associated with microglial activation. The inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) undergoes oligomerization upon inflammasome activation, resulting in the formation of ASC specks. These structures are recognized by microglia as damage-associated molecular patterns (DAMPs), thereby promoting inflammatory signaling. Recent studies have demonstrated that extracellular ASC specks associate with amyloid-{beta} (A{beta}), and that uptake of ASC-A{beta} composites by microglia amplifies pro-inflammatory responses. Although ASC specks have also been shown to potentiate -synuclein (Syn) preformed fibril-induced pathology, their interaction with monomeric Syn and their effects on inflammasome activation remain poorly understood. Here, we co-stimulated murine SIM-A9 microglia with ASC-Syn assemblies and evaluated their effects on NLRP3 inflammasome activation. Electron microscopy revealed a close association between ASC fibrils and Syn monomers. Exposure of microglia to ASC-Syn enhanced NLRP3 inflammasome activation, as evidenced by increased ASC speck formation, caspase-1 activation, and secretion of IL-1{beta} and IL-18, when compared to ASC or Syn alone. In addition, immunohistochemical analyses of post mortem brain tissue from patients with dementia with Lewy bodies demonstrated ASC expression in regions exhibiting Syn pathology and showed ASC co-localization with Syn within Lewy bodies. Collectively, these findings identify ASC-Syn assemblies as potent amplifiers of NLRP3 inflammasome signaling and suggest a mechanism through which they may contribute to sustained neuroinflammation in synucleinopathies.

neuroscience↗

bioRxiv2023

Efficient formation and maintenance of humoral and CD4 T cell immunity targeting the viral capsid in acute-resolving hepatitis E infection

Background and aimsCD4 T cells shape the neutralizing antibody (nAb) response and facilitate viral clearance in various infections. Knowledge of their phenotype, specificity and dynamics in hepatitis E virus (HEV) infection is limited. HEV is enterically transmitted as a naked virus (nHEV) but acquires a host-derived quasi-envelope (eHEV) when budding from cells. While nHEV is composed of the open-reading-frame (ORF)-2-derived capsid, eHEV particles also contain ORF3-derived proteins. We aimed to longitudinally characterize the HEV-specific CD4 T cells and neutralizing antibodies that target either nHEV or eHEV particles in immunocompetent individuals with acute and resolved HEV infection. MethodsHEV-specific CD4 T cells were analyzed by intracellular cytokine staining after stimulation with in silico predicted ORF1- and ORF2-derived epitopes and overlapping peptides spanning the ORF3 region. Ex vivo multi-parametric characterization of capsid-specific CD4 T cells was performed using customized MHC class II tetramers. Total and neutralizing antibodies targeting nHEV or eHEV particles were determined. ResultsHEV-specific CD4 T cell frequencies and antibody titers are highest in individuals with acute infection and decline in a time-dependent process with an antigen hierarchy. HEV-specific CD4 T cells primarily target the ORF2-derived capsid, which correlates with the presence of nAbs targeting nHEV. In contrast, ORF3-specific CD4 T cells are hardly detectable and eHEV is less efficiently neutralized. Capsid-specific CD4 T cells undergo memory formation and stepwise contraction, accompanied by dynamic phenotypical and transcriptional changes over time. ConclusionThe viral capsid is the main target of HEV-specific CD4 T cells and antibodies in acute resolving infection, correlating with efficient neutralization of nHEV. Capsid-specific immunity rapidly emerges followed by a stepwise contraction for several years after infection. Impact and implicationsThe interplay of CD4 T cells and neutralizing antibody responses is critical in the host defense against viral infections, yet little is known about their characteristics in hepatitis E virus (HEV) infection. We conducted a longitudinal study of immunocompetent individuals with acute and resolved HEV infection to understand the characteristics of HEV-specific CD4 T cells and neutralizing antibodies targeting different viral proteins and particles. We found that HEV-specific CD4 T cells mainly target the viral capsid, leading to efficient neutralization of the naked virus (nHEV) while the quasi-envelope (eHEV) particles are less susceptible to neutralization. As individuals with pre-existing liver disease and immunocompromised individuals are at risk for fulminant or chronic courses of HEV infection, these individuals might benefit from the development of vaccination strategies which require a detailed knowledge of HEV-specific CD4 T cell and antibody immunity.

immunology↗

bioRxiv2021

Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimers disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-{gamma} with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and {beta}-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=-0.874, p<0.0001) but not in vehicle controls (R=-0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar {beta}-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.

neuroscience↗

bioRxiv2021

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

BackgroundWe undertook longitudinal {beta}-amyloid positron emission tomography (A{beta}-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist pioglitazone in A{beta} model mice. We thus tested the hypothesis this treatment would rescue from increases of the A{beta}-PET signal while promoting spatial learning and preservation of synaptic density. MethodsPS2APP mice (N=23; baseline age: 8 months) and AppNL-G-F mice (N=37; baseline age: 5 months) were investigated longitudinally for five months using A{beta}-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. ResultsSurprisingly, A{beta}-PET and immunohistochemistry revealed a shift towards higher fibrillary composition of A{beta}-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. ConclusionThese translational data suggest that a shift towards higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the A{beta}-PET signal upon immunomodulatory treatments targeting A{beta} aggregation can thus be protective.

neuroscience↗

bioRxiv2020

Winners and losers over 35 years of dragonfly and damselfly distributional change in Germany

Recent studies suggest insect declines in parts of Europe; however, the generality of these trends across different taxa and regions remains unclear. Standardized data are not available to assess large-scale, long-term changes for most insect groups but opportunistic citizen science data is widespread for some taxa. We compiled over 1 million occurrence records of Odonata (dragonflies and damselflies) from different regional databases across Germany. We used occupancy-detection models to estimate annual distributional changes between 1980 and 2016 for each species. We related species attributes to changes in the species distributions and inferred possible drivers of change. Species showing increases were generally warm-adapted species and/or running water species while species showing decreases were cold-adapted species using standing water habitats such as bogs. We developed a novel approach using time-series clustering to identify groups of species with similar patterns of temporal change. Using this method, we defined five typical patterns of change for Odonata - each associated with a specific combination of species attributes. Overall, trends in Odonata provide mixed news - improved water quality, coupled with positive impacts of climate change, could explain the positive trend status of many species. At the same time, declining species point to conservation challenges associated with habitat loss and degradation. Our study demonstrates the great value of citizen science data for assessing large-scale distributional change and conservation decision-making.

ecology↗

bioRxiv2020

The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation

Evidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 {+/-} 0.024 L/g-min and 0.294 {+/-} 0.032 L/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10th the amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗