Biology subjects

Hartmann, V.

Publications and source records attributed to Hartmann, V..

3 recordsLinked to original sources

bioRxiv2025

In pemphigus, cell detachment, but not autoantibody binding, induces cell-wide, long-lasting transcriptomic and proteomic changes

Desmoglein 1 (DSG1) and desmoglein 3 (DSG3) are adhesion molecules that maintain intercellular connections between epidermal, hair follicle, and mucosal keratinocytes. Autoantibodies (AAbs) targeting these molecules ultimately lead to the blister formation characteristic of pemphigus vulgaris (PV) or pemphigus foliaceus (PF). To investigate the molecular events following autoantibody binding up to 48 hours, we quantified transcriptome and proteome dynamics during split formation in a human skin organ culture (HSOC) model for PV and in a 2D cell-culture model for PV and endemic PF. Treatment of the cells in 2D culture with PX43, a single-chain variable fragment targeting DSG1/3, or with endemic PF anti-DSG1 IgG yielded neither a significant transcriptome nor a proteome response over time relative to the respective IgG controls. When treating the HSOC model with mouse antibody AK23 (targeting DSG3) or with PX43, only the latter induced split formation. In the absence of split formation, no differentially regulated pathways were detected at the transcriptomic level. Split formation, observed as early as 5 hours post-injection, was associated with significant and sustained upregulation of IFN{gamma} and TNF-related genes, mediated by upstream NF{kappa}B, MAPK, and JAK-STAT pathways. The gene expression changes, corroborated by proteomics data, were strongly correlated with early wounding and keratinocyte detachment, as well as the transcriptome profile in the skin from PV patients, while inversely associated with keratinocyte differentiation and cell stretching. The co-occurrence of well-wide and long-lasting transcriptome and proteome responses with split formation suggests that PF-IgG and PV-related AAbs neither induce downstream transcriptome nor proteome changes directly. Rather, these changes appear to be secondary effects resulting from reduced adhesion and mechanical-stress-induced split formation of keratinocytes in vitro and most likely in patient skin in vivo.

immunology↗

bioRxiv2021

Murine norovirus capsid plasticity - Glycochenodeoxycholic acid stabilizes P domain dimers and triggers escape from antibody recognition

The murine norovirus (MNV) capsid protein is the target for various neutralizing antibodies binding to distal tips of its protruding (P)-domain. The bile acid glycochenodeoxycholic acid (GCDCA), an important co-factor for murine norovirus (MNV) infection, has recently been shown to induce conformational changes in surface-loops and a contraction of the virion. Here, we employ protein NMR experiments using stable isotope labeled MNV P-domains to shed light on underlying molecular mechanisms. We observe two separate sets of NMR resonance signals for P-domain monomers and dimers, permitting analysis of the corresponding exchange kinetics. Unlike human norovirus GII.4 P-dimers, which exhibit a half-life in the range of several days, MNV P-dimers are very short lived with a half-life of about 17 s. Addition of GCDCA shifts the equilibrium towards the dimeric form by tightly binding to the P-dimers. In MNV virions GCDCA-mediated stabilization of the dimeric arrangement of P-domains generates a more ordered state, which in turn may entropically assist capsid contraction. Numerous long-range chemical shift perturbations (CSPs) upon addition of GCDCA reflect allosteric conformational changes as a feature accompanying dimer stabilization. In particular, CSPs indicate rearrangement of the EF loop, a target for various neutralizing antibodies. Indeed, treating MNV virions with GCDCA prior to neutralizing antibody exposure abolishes neutralization. These findings advance our understanding of GCDCA-induced structural changes of MNV capsids and experimentally support an intriguing viral immune escape mechanism relying on GCDCA-triggered conformational changes of the P-dimer. Significance StatementThis study sheds light on the role of glycochenodeoxycholic acid (GCDCA) in promoting murine norovirus (MNV) infection and immune escape. Binding of GCDCA to the dimeric P-domain has been well characterized by crystallography and cryo EM studies, showing that upon GCDCA binding, a 90{degrees} rotation of the P-domain occurs, which results in its collapse onto the underlying shell of the virus. Our NMR experiments now reveal P-dimer stability as a new dimension of plasticity of MNV capsids and suggest that capsid contraction is entropically assisted. Conformational changes as a feature of P-dimer stabilization eliminate recognition by neutralizing antibodies, no longer being able to prevent infection. These findings highlight key differences between human and MNV capsid structures, promote our understanding of MNV infection on a molecular level, and reveal a novel immune escape mechanism.

biochemistry↗

bioRxiv2020

Marine reserve benefits and recreational fishing yields: the winners and the losers

Marine reserves constitute effective tools for preserving fish stocks and associated human benefits. However, not all reserves perform equally, and predicting the response of marine communities to management actions in the long run is challenging. Our decadal-scale survey of recreational fishing yields at Frances 45-year old Cerbere-Banyuls marine reserve indicated significant protection benefits, with 40-50% higher fishing yields per unit effort in the partial-protection zone of the reserve (where fishing is permitted but at a lower level) than in surrounding non-reserve areas. Over the period 2005-2014, catch per unit effort (CPUE) showed a similar pattern of decline inside and outside the reserve while weight per unit effort (WPUE) increased by 131% inside and decreased by 60% outside. Different CPUE and WPUE trajectories among fish families indicated changing catch assemblages, with yields increasing for the family most valued by fisheries, Sparidae (the ecological winners). However, reserve benefits were restricted to off-shore fishermen (the social winners), as on-shore yields were [~]4 times lower and declining, even inside the reserve. Our study illustrates how surveys of recreational fishing yields can help evaluate the effectiveness of marine protected areas for key social and ecological protagonists. We show that, more than four decades after its establishment, fishing efficiencies at the historical Cerbere-Banyuls marine reserve are still changing, but benefits in terms of catch abundance, weight, and composition remain predominantly restricted to off-shore fishermen. Further regulations appear necessary to guarantee that conservation strategies equitably benefit societal groups.

ecology↗