Biology subjects

Klotz, L.

Publications and source records attributed to Klotz, L..

9 recordsLinked to original sources

bioRxiv2026

A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity

T and B cell-mediated immunosurveillance of the central nervous system (CNS) can become maladaptive in multiple sclerosis (MS). Epstein-Barr virus (EBV) is a likely driver of MS, yet how exactly EBV-specific T cells contribute remains unclear. We generated an antigen-resolved atlas of blood and cerebrospinal fluid (CSF) T cells from untreated MS patients and controls. T cell clones carrying a GZMK effector-memory program in blood were CSF-biased, particularly in MS, and associated with EBV reactivity. In CSF, EBV-reactive GZMK CD8 T cells engaged B lineage cells. Activated CD8 T cells promoted atypical B cell and plasmablast formation, whereas GZMK-enriched effector-memory cells induced IL-6 and IL-8 release from myeloid cells. Together, these findings identify an infection-imprinted, CNS-biased state and support a model in which EBV-specific CD8 T cells contribute to inflammation through a non-canonical mode of B cell and myeloid cell activation.

immunology↗

bioRxiv2026

Performance-impacting brain state maladaptation driving disease progression in early mouse and human neuroinflammation

The neuronal mechanisms driving progression in neuroinflammatory disorders from early relapse-remitting phases to later neurodegenerative phases remain largely elusive. Functional brain state shifts towards hyperactivity, persisting beyond relapses, represent an early maladaptive response. Here, in remission stage of an experimental autoimmune encephalitis (EAE) mouse model of RRMS, we identified a reduced excitability upon optogenetic stimulation in the brain stem, the area of active disease, while in the cortex a persistent cortical neuronal hyperactivity and synaptic remodeling emerged, accompanied with an increase of markers of early apoptosis. In contrast, hippocampal circuits, which undergo a functional state shift without hyperactivity, do not show increased apoptosis. Visual cortical networks showed a deterioration of the accuracy of encoding visual information and a decrease in the behavioural visual discrimination ability in mice. In RRMS patients in remission, we identified a reduced visual colour discrimination, indicating both the presence and the clinical relevance of early brain state maladaptation that may contribute to progression independent from relapse activity (PIRA). SummaryIn a RRMS model and in patients, impaired visual processing was reported, indicating brain state maladaptations, associated with persistent cortical hyperactivity, brain stem hypoactivity, synaptic remodeling, and apoptosis. These maladaptations might contribute to relapse-independent disease progression through sustained network dysfunction.

neuroscience↗

bioRxiv2026

Histone neutralization protects the ischemic brain against stroke-associated pneumonia

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients and mice exposed to middle cerebral artery occlusion, we show that stroke-associated pneumonia markedly worsens clinical stroke outcome. In mice, pneumonia induced 3 days after stroke impaired neurological recovery and increased brain neutrophil infiltrates, blood-brain barrier breakdown, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Neutrophils were critical mediators of pneumonia-induced blood-brain barrier breakdown and microvascular thrombosis. Notably, administration of a neutralizing anti-histone antibody during pneumonia--unlike degradation or blockade of neutrophil extracellular trap formation or myeloperoxidase inhibition--restored long-term neurological recovery and prevented brain atrophy in stroke-associated pneumonia mice. This study identifies extracellular histones as key drivers of secondary inflammatory brain injury and establishes histone neutralization as a therapeutic strategy with an extended treatment window in the post-acute stroke phase. One Sentence SummaryNeutralizing extracellular histones reverses pneumonia-driven secondary brain injury and restores long-term recovery after ischemic stroke.

neuroscience↗

bioRxiv2025

The nuclear receptor NR4A1 serves as a neutrophil-intrinsic regulator mitigating stroke severity

Ischemic stroke is accompanied by recruitment and activation of immune cells which play an important role in the progression of the brain damage. The nuclear receptor NR4A1 emerged as a key regulator within the inflammatory response of several immune diseases by regulating immune cell activation. In this study, we investigated the role of NR4A1 in the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage-limiting effect after stroke. This effect is largely mediated by neutrophil recruitment and importantly, NR4A1 activation with its ligand Cytosporone B improves functional outcome and reduces brain damage. Modulation of NR4A1 is therefore a promising therapeutic target for the treatment of the nuclear receptor NR4A1 in the activation and recruitment of peripheral and brain resident immune cells after cerebral ischemia and its consequences for stroke outcome. We demonstrate that NR4A1 ablation augments neutrophil activation and CNS recruitment within days after stroke thereby increasing infarct size, CNS inflammation, neuronal damage and deteriorating functional outcome. This effect is mediated via modulation of cell-intrinsic neutrophil function and maturation as illustrated by neutrophil-specific NR4A1 ablation and mixed bone-marrow chimera experiments. Notably, the NR4A1 agonist Cytosporone B reduced CNS neutrophil infiltration, infarct size and functional outcome after stroke in a bicentric preclinical stroke trial, demonstrating that NR4A1-mediated control of neutrophil reactivity is amenable to pharmacological modulation. In humans, NR4A1 expressing neutrophils are present in the peripheral blood of stroke patients and neutrophil NR4A1 expression correlates with improved long-term outcome after 3 months. Furthermore, NR4A1 expression in brain parenchyma neutrophils is negatively correlated with neuronal cell loss, illustrating a role of NR4A1 in regulating neutrophil mediated neuronal cell death in human stroke. Together our data reveal the nuclear factor NR4A1 as a brake of intrinsic neutrophil activity controlling neutrophil-mediated brain inflammation and neurotoxicity in stroke which may serve as a novel therapeutic target to limit inflammation-associated augmentation of ischemic damage after stroke.

neuroscience↗

bioRxiv2024

Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1+CD56+ NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimers disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

immunology↗

bioRxiv2024

Epitranscriptomic rRNA fingerprinting reveals tissue-of-origin and tumor-specific signatures

Mammalian ribosomal RNA (rRNA) molecules are highly abundant RNAs, decorated with over 220 rRNA modifications. Previous works have shown that some rRNA modification types can be dynamically regulated; however, how and when the mammalian rRNA modification landscape is remodeled remains largely unexplored. Here, we employ direct RNA nanopore sequencing to chart the human and mouse rRNA epitranscriptome across tissues, developmental stages, cell types and disease. Our analyses reveal multiple rRNA sites that are differentially modified in a tissue- and/or developmental stage-specific manner, including previously unannotated modified sites. We demonstrate that rRNA modification patterns can be used for tissue and cell type identification, which we hereby term epitranscriptomic fingerprinting. We then explore rRNA modification patterns in normal-tumor matched samples from lung cancer patients, finding that epitranscriptomic fingerprinting accurately classifies clinical samples into normal and tumor groups from only 250 reads per sample, demonstrating the potential of rRNA modifications as diagnostic biomarkers.

molecular biology↗

bioRxiv2024

Treatment with 2-phospho-L-ascorbic acid mitigates biochemical phenotypes of heme oxygenase 1 deficiency

Heme oxygenase 1 (HO-1) deficiency is a fatal genetic disorder characterized by impaired heme catabolism, leading to excessive oxidative damage and cell death. Despite evidence from non-human models suggesting mitochondrial dysfunction, the precise pathomechanisms in humans remain unclear, resulting in a lack of effective treatments. Using patient-derived lymphoblastoid cells and HO-1 knockout HEK293T cell models, we demonstrate that HO-1 deficiency is associated with altered mitochondrial morphology and impaired mitochondrial function. Furthermore, it is linked to significant ascorbic acid depletion, accompanied by compensatory upregulation of SVCT2, a key ascorbic acid transporter. Treatment with 2-phospho-L-ascorbic acid, a stable vitamin C analog, restores intracellular ascorbic acid levels and protects cells from hemin-induced cytotoxicity, highlighting its potential as a novel therapeutic strategy for HO-1 deficiency. Our study underscores the critical role of oxidative stress and mitochondrial dysfunction in HO-1 deficiency, paving the way for targeted interventions in this devastating disorder.

molecular biology↗

bioRxiv2022

Glycolytic interference blocks influenza A virus propagation by impairing viral polymerase-driven synthesis of genomic vRNA

Influenza A virus (IAV), like any other virus, provokes considerable modifications of its host cells metabolism. This includes a substantial increase in the uptake as well as the metabolization of glucose. Although it is known for quite some time that suppression of glucose metabolism restricts virus replication, the exact molecular impact on the viral life cycle remained enigmatic so far. Using 2-deoxy-D-glucose (2-DG) we examined how well inhibition of glycolysis is tolerated by host cells and which step of the IAV life cycle is affected. We observed that effects induced by 2-DG are reversible and that cells can cope with relatively high concentrations of the inhibitor by compensating the loss of glycolytic activity by upregulating other metabolic pathways. Moreover, mass spectrometry data provided information on various metabolic modifications induced by either the virus or agents interfering with glycolysis. In the presence of 2-DG viral titers were significantly reduced in a dose-dependent manner. The supplementation of direct or indirect glycolysis metabolites led to a partial or almost complete reversion of the inhibitory effect of 2-DG on viral growth and demonstrated that indeed the inhibition of glycolysis and not of N-linked glycosylation was responsible for the observed phenotype. Importantly, we could show via conventional and strand-specific qPCR that the treatment with 2-DG led to a prolonged phase of viral mRNA synthesis while the accumulation of genomic vRNA was strongly reduced. At the same time, minigenome assays showed no signs of a general reduction of replicative capacity of the viral polymerase. Therefore, our data suggest that the significant reduction in IAV replication by glycolytic interference occurs mainly due to an impairment of the dynamic regulation of the viral polymerase which conveys the transition of the enzymes function from transcription to replication. Author SummaryUpon infection the influenza A virus alters the metabolism of infected cells. Among others, this includes a pronounced increase in glucose metabolism. We aimed to get a better understanding of these metabolic virus-host interactions and to unravel the mechanism by which glycolytic inhibition impairs the viral life cycle. On the one hand, we observed a virus-induced upregulation of many glycolysis metabolites which could often be reversed by the administration of a glycolysis inhibitor. On the other hand, our data suggested that the inhibitor treatment severely impaired viral propagation by interfering with the regulation of the viral polymerase. This manifested in an extended phase of transcription, while replication was strongly reduced. Additionally, we assessed the safety and tolerability of the used drug in immortalized and primary cells. Our study sheds more light on metabolic virus-host interactions and provides a better understanding of metabolic interference as a potential host-targeted antiviral approach, which does not bear the risk of creating resistances.

microbiology↗

bioRxiv2022

The nuclear receptor NR4A1 restrains neutrophil granulocyte mediated brain damage in cerebral ischemia

Immigration and activation of immune cells play a significant role in damage progression after ischemic stroke. It has been shown that the nuclear receptor NR4A1 exerts a crucial role within the inflammatory response of various immune diseases via regulating immune cell activation. In this study, we investigated the role of NR4A1 on the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage limiting effect after ischemic stroke through immigrating neutrophil granulocytes. Importantly, NR4A1-activation with its ligand Cytosporone-B improves functional outcome and diminishes brain damage. Therefore, modulation of NR4A1 is a promising therapeutic target in the treatment of stroke.

neuroscience↗