Biology subjects

Pritsch, M.

Publications and source records attributed to Pritsch, M..

4 recordsLinked to original sources

bioRxiv2025

RIG-I-like receptor-dependent type I Interferon regulates antigen dose and activation in yellow fever vaccine 17D-infected antigen presenting cells

The live-attenuated yellow fever vaccine 17D-204 (YF17D) activates robust innate immune responses followed by rapid induction of adaptive immunity resulting in long-lasting protection. YF17D triggers the production of type I interferons (IFNs) which have a dual role in antigen presenting cells regulating their infection and contributing to their activation. Infection with YF17D was detected in primary human blood monocytes and conventional dendritic cells (DCs) and in monocyte-derived DCs but was highly restricted by type I IFN. Blocking IFNAR signaling in YF17D-infected PBMC from vaccinated donors resulted in increased activation of YF17D-specific CD8+ T cells. Consistently, peak IFN-alpha plasma levels correlated inversely with the CD8+ T cells response in YF17D vaccinees. Loss of function experiments demonstrated a dominant role of retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and mitochondrial antiviral signaling protein (MAVS) for type I IFN induction and restriction of YF17D. The type I IFN response was mediated by 5 tri- or diphosphate dsRNA intermediates that are formed during YF17D infection. In vivo proximity labelling (IPL) of RIG-I and next-generation sequencing confirmed interaction of RIG-I with YF17D-dsRNA in infected cells. Thus, YF17D-triggered RLR-signaling restricts viral replication through type I IFN and thus limits the production of viral antigens that can be presented to T cells.

immunology↗

bioRxiv2025

A Data-Driven Closed-Loop Control Approach to Drive NeuralState Transitions for Mechanistic Insight

Repetitive negative thinking (RNT) is a transdiagnostic risk factor for mood disorders, consistently associated with altered biological substrates, including functional connectivity in key brain networks. As a stable cognitive feature linked to vulnerability across disorders, RNT presents a compelling target for intervention. However, leveraging RNT as a modifiable mechanism requires a deeper understanding of its causal neural dynamics and how targeted modulation can induce adaptive change. We introduce a data-driven framework that combines dynamical system reconstruction (DSR) with model predictive control (MPC) to infer optimal control policies for transitions between resting and sad mood brain states from functional magnetic resonance imaging (fMRI) data. Using nonlinear generative DSR models trained on individuals with remitted major depressive disorder (rMDD) and matched healthy controls (HCs), we derive region-specific, state-dependent control strategies. We find that small brain regions (e.g., sgACC, NAcc) exhibit higher controllability, requiring less energy to drive state transitions. Critically, rMDD participants require less control energy than HCs to move into sad mood from rest and - unexpectedly - also to move back to rest, though the latter effect is spatially restricted. Despite comparable target attainment, rMDD participants remain closer to the sad mood distribution when returning to rest, indicating a residual negative-affect bias. Our data-driven analysis reveals elevated effective coupling in rMDD, most prominently toward (but not away from) the DLPFC. Across regions, greater coupling is associated with reduced control energy, suggesting that enhanced network influence facilitates more efficient state transitions. These results suggest dynamics in rMDD that facilitate entry into negative affect and hinders full disengagement without sustained input, highlighting closed-loop control as a tool for mechanistic insight and potentially for designing targeted neuromodulatory interventions in the future.

neuroscience↗

bioRxiv2024

Interferon-induced activation state of circulating dendritic cells and monocytes triggered by yellow fever vaccination correlates with early protective antibody responses

Yellow fever vaccination provides long-lasting protection and is a unique model for studying the immune response to an acute RNA virus infection in humans. To elucidate the early innate immune events preceding the rapid generation of protective immunity, we performed transcriptome analysis of human blood dendritic cell (DC) and monocyte subpopulations before and 3, 7, 14 and 28 days after vaccination. We detected temporary upregulation of IFN-stimulated genes (ISG) in all DC and monocyte subsets on day 3 and 7 after vaccination as well as cell type specific responses and temporal dynamics. Single cell RNA sequencing revealed rapid appearance of activated DC and monocyte clusters dominated by ISGs, inflammatory chemokines and genes involved in antigen processing and presentation. This was confirmed by flow cytometric analysis in a large cohort of vaccinees. We identified SIGLEC1/CD169 upregulation as a sensitive indicator of the transient IFN-induced activation state elicited in DCs and monocytes by YF17D vaccination correlating with early protective IgM antibody responses.

immunology↗

bioRxiv2023

Prior flavivirus immunity skews the yellow fever vaccine response to expand cross-reactive antibodies with increased risk of antibody dependent enhancement of Zika and dengue virus infection

Human pathogenic flaviviruses pose a significant health concern and vaccination is the most effective instrument to control their circulation. How pre-existing immunity to antigenically related viruses modulates immunization outcome remains poorly understood. In this study, we evaluated the effect of vaccination against tick-borne encephalitis virus (TBEV) on the epitope immunodominance and immunogenicity of the yellow fever 17D vaccine (YF17D) in a cohort of 250 human vaccinees. Following YF17D vaccination, all study participants seroconverted and generated protective neutralizing antibody titers. At day 28, TBEV pre-immunity did not affect the polyclonal neutralizing response which largely depended on the IgM fraction. We found that sera from TBEV-immunized individuals enhanced YF17D vaccine virus infection via antibody-dependent enhancement (ADE). Upon vaccination, individuals with TBEV pre-immunity had higher concentrations of cross-reactive IgG antibodies with limited neutralizing capacity against YF17D whereas vaccinees without prior flavivirus exposure showed a non-cross-reacting response. Using a set of recombinant YF17D envelope protein mutants displaying different epitopes, we identified quaternary epitopes as the primary target of neutralizing antibodies. Sequential immunizations redirected the IgG response towards the pan-flavivirus fusion loop epitope (FLE) with the potential to mediate enhancement of dengue and Zika virus infections whereas TBEV naive individuals elicited an IgG response directed towards neutralizing epitopes without an enhancing effect. We propose that the YF17D vaccine effectively conceals the FLE and primes a neutralizing IgG response in individuals with no prior flavivirus exposure. In contrast, the response in TBEV-experienced recipients favors weakly-neutralizing, cross-reactive epitopes potentially increasing the risk of severe dengue and Zika disease due to ADE.

immunology↗