Biology subjects

Kaiser, R.

Publications and source records attributed to Kaiser, R..

8 recordsLinked to original sources

bioRxiv2026

Hepatitis C virus replication fitness as a determinant of antiviral therapy outcome

Background and AimsHepatitis C virus (HCV) infections were previously treated with interferon (IFN) but today direct acting antivirals (DAAs) with cure rates >95% are available. DAA treatment failure is primarily attributed to resistance associated mutations (RAMs), often imposing a fitness cost. Interferon treatment outcome was shown to be associated with the interferon sensitivity determining region (ISDR), which is part of the replication enhancing domain (ReED) in non-structural protein (NS) 5A. We found that accumulation of mutations in the ReED was indicative of elevated viral genome replication fitness. This study investigates the impact of HCV replication fitness on antiviral treatment outcomes. MethodsWe utilized chimeric HCV subgenomic replicons containing RAMs and ReED sequences from patients after interferon treatment or DAA failure to assess replication fitness of patient isolates in presence and absence of inhibitors. ResultsReplication fitness did not impact on IFN sensitivity in cell culture but resulted in higher remaining antigen levels for highly replicating variants at a given IFN concentration. Furthermore, we identified ReED variants substantially increasing HCV replication in several patients who failed DAA therapy across different genotypes. High replicator ReEDs rescued the fitness loss caused by RAMs like Y93C/H (NS5A) and S282T (NS5B). While high replication fitness did not intrinsically increase drug sensitivity (IC50), it allowed the virus to sustain robust replication despite antiviral pressure. ConclusionsElevated replication fitness might support interferon treatment due to increased antigen presentation, facilitating adaptive immune responses. Furthermore, ReED mediated increase in replication fitness could contribute to DAA treatment failure by preserving higher replication upon treatment and compensating for RAM associated fitness costs. Thus, patients failing DAA treatment should be monitored for RAMs and ReED mutations.

microbiology↗

bioRxiv2025

From rest to focus: Pharmacological modulation of the relationship between resting state dynamics and task-based brain activation

Dynamic resting-state brain activity provides insight into intrinsic neural function and holds promise for predicting individual responses to cognitive demands and pharmacological interventions. This research could ultimately guide medication selection, yet links between network dynamics and medication effects on cognitive function require further validation. Here, we examined whether dynamic activity of an attentional network at rest relates to task-evoked brain activation on the Multi Source Interference Task (MSIT) following administration of methylphenidate (20mg) and haloperidol (2mg), which have opposing effects on attention and catecholaminergic function. Fifty-nine healthy adults completed resting-state and task-based fMRI on three separate days on which they received methylphenidate, haloperidol, or placebo in a double-blind placebo-controlled design. Coactivation pattern analysis determined time spent in the dorsal attention network (DAN) under placebo at rest. Linear mixed-effects modelling assessing the relationship between MSIT task activation under drug and time spent in DAN at rest under placebo and MSIT task activation under drug identified a significant interaction in the dorsolateral prefrontal cortex (dlPFC; p<0.001). Post-hoc analyses indicated that more time in the DAN at rest under placebo was associated with decreased MSIT dlPFC activation under methylphenidate and increased dlPFC activation under haloperidol. Findings demonstrate that resting dynamics of an attentional network are linked to task-related brain responses under different drug conditions within a region implicated in attentional control and sensitive to catecholaminergic variance. Resting-state dynamics may predict pharmacological modulation of goal-directed cognition, highlighting the potential clinical utility of resting-state dynamics in predicting medication response and supporting individualized treatment.

neuroscience↗

bioRxiv2025

Geno2pheno: Interpretable and accurate HIV antibody resistance prediction

BackgroundAntiretroviral therapy (ART) is a life saving option for people living with HIV-1 (PLWH) and is effective against many viral strains. The most common ARTs involve combinations of drugs targeting viral or cellular proteins. Most of these drugs have to be taken daily. An alternative to ARTs with established inhibitors comprises broadly neutralizing antibodies (bNAbs). However, bNAbs share the problem of viral resistance with protein inhibitors. We developed a web service geno2pheno[bNAbs] that allows users to upload viral genotypes and estimates the respective resistance to many common bNAbs. The service uses trained statistical models to classify the virus into sensitive and resistant, respectively or to regress the IC50. MethodsWe used two linear models as well as two neural nets for each task and multi-task (MT) learning to train both models for IC50 prediction and classification simultaneously. During multi-task learning we penalize divergence of class and IC50 score in addition to the loss individual to each of the models. FindingsWe compared the linear models of geno2pheno[bNAbs] to other state-of-the-art methods like recurrent neural nets and self-attention, and found them to be competitive in regard to accuracy and have the benefit of fast computation and being easily interpretable in regard to features, i.e., positions on the envelope. InterpretationWe developed a web service for the prediction of antibody resistance (geno2pheno[bNAbs]) to HIV-1, which is free to use and can be extended to other viruses, like Sars-Cov2, in the future.

bioinformatics↗

bioRxiv2024

Cytosolic sodium accumulation is a cellular danger signal triggering endocytic dysfunction and NLRP3 inflammasome activation

Detecting and responding to noxious molecules internalized within the endolysosomal system, including bacterial toxins and particulate matter, is essential to prevent cellular intoxication and damage. Here, we demonstrate that the NLRP3 inflammasome detects perturbations of the endolysosomal system by large clostridial toxins, including toxin B from Clostridioides difficile, as well as monosodium urate and silica crystals in human macrophages. These molecules cause sodium efflux from the endolysosomal system into the cytosol, driving cytosolic sodium accumulation. The rapid increase in cytosolic sodium subsequently triggers cell swelling and inhibits endocytic trafficking to activate the NLRP3 inflammasome. Furthermore, we demonstrate that cytosolic sodium accumulation is a common trigger for NLRP3 activation by non-particulate stimuli, including nigericin and inhibition of the Na+/K+ ATPase. Our findings reveal that accumulation of cytosolic sodium is the common denominator underlying activation of the NLRP3 inflammasome upon exposure to different danger signals.

immunology↗

bioRxiv2024

Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis

AbstractThrombotic diseases remain the major cause of death and disability worldwide with insufficient preventive and therapeutic strategies available. In the last decades a prominent inflammatory component has been identified as a key driver in the initiation and propagation of thrombosis - named thromboinflammation. However, a comprehensive investigation of the human immune system in thromboinflammation, beyond histological quantification, is lacking, which is essential for the development of novel therapeutic approaches. We therefore mapped the trajectories, functional states, and intercommunication of immune cells in stroke thrombi, retrieved by thrombectomy, at single-cell resolution. We reveal distinct leukocyte subpopulations with prothrombotic and, surprisingly, prominent fibrinolytic properties characterized by aberrant activation of intracellular host defense as well as hypoxia induced pathways. A prominent thrombolytic PLAUhigh, PLAURhigh, THBDhigh thrombus neutrophil subset, also expressing high levels of pro-recanalizing VEGFA and VEGFB, dominated the thrombus neutrophil environment. On the other hand CD16high NR4A1high non-classical monocytes with strong CXCL8, CXCL2, CXCL1 and CXCL16 mediated neutrophil- attracting and PLAU, PLAUR, THBD and TFPI mediated thrombolytic properties defined the thrombus monocyte environment. These thrombus monocyte subsets were characterized by high expression of TIMP1 and TREM1. These novel innate immune- cell subsets provide insights into the thrombogenic and pro-resolving properties of innate immune-cells. To provide mechanistic insight into these multi-omic findings, we utilized reverse translation approaches. In vitro as well as murine in vivo thrombosis models underlined the causal relevance of these immune-cell axes for thrombolysis: NR4A1high thrombus monocytes acquired a neutrophil-chemoattractive transcriptomic phenotype, neutrophils continuously infiltrated established murine thrombi in vivo and acquired a HIF1-mediated thrombolytic phenotype in vitro. A depletion of NR4A1high thrombus monocytes reduced thrombus neutrophil influx and exacerbated thrombosis in vivo. Together, this unravels cross-communicating monocyte and neutrophil subsets with thrombus-resolving properties and provide a publicly accessible immune-landscape of thrombosis. This provides a valuable resource for future research on thrombo- inflammation and might pave the way for novel immune-modulatory approaches for prevention or resolution of thrombosis.

immunology↗

bioRxiv2021

Thrombocytopenia and splenic platelet directed immune responses after intravenous ChAdOx1 nCov-19 administration

Summary paragraphVaccines against SARS-CoV-2 are based on a range of novel vaccine platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently a rare and novel complication of SARS-CoV-2 targeted adenovirus vaccines has emerged: thrombosis with thrombocytopenia syndrome (TTS). TTS is characterized by low platelet counts, clot formation at unusual anatomic sites and platelet-activating PF4-polyanion antibodies reminiscent of heparin-induced thrombocytopenia. Here, we employ in vitro and in vivo models to characterize the possible mechanisms of this platelet-targeted autoimmunity. We show that intravenous but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation. After intravenous injection, these aggregates are phagocytosed by macrophages in the spleen and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of TTS and highlights accidental intravenous injection as potential mechanism for post-vaccination TTS. Hence, safe intramuscular injection, with aspiration prior to injection, could be a potential preventive measure when administering adenovirus-based vaccines.

immunology↗

bioRxiv2021

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients. We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls. We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction.

immunology↗

bioRxiv2018

The RNA-binding protein AATF coordinates rRNA maturation

AATF is a central regulator of the cellular outcome upon p53 activation, a finding that has primarily been attributed to its function as a transcription factor. Recent data showed that AATF is essential for ribosome biogenesis and plays a role in rRNA maturation. AATF has been implicated to fulfil this role through direct interaction with rRNA and was identified in several RNA-interactome capture experiments. Here, we provide a first comprehensive analysis of the RNA bound by AATF using CLIP-sequencing. Interestingly, this approach shows predominant binding of the 45S pre-ribosomal RNA precursor molecules. Furthermore, AATF binds to mRNAs encoding for ribosome biogenesis factors as well as snoRNAs. These findings are complemented by an in-depth analysis of the protein interactome of AATF containing a large set of proteins known to play a role in rRNA maturation with an emphasis on the protein-RNA-complexes known to be required for the generation of the small ribosomal subunit (SSU). In line with this finding, the binding sites of AATF within the 45S rRNA precursor localize in close proximity to the SSU cleavage sites. Consequently, our multilayer analysis of the protein-RNA interactome of AATF reveals this protein to be an important hub for protein and RNA interactions involved in ribosome biogenesis.

molecular biology↗