Biology subjects

Zimmermann, L.

Publications and source records attributed to Zimmermann, L..

12 recordsLinked to original sources

bioRxiv2026

A transcriptional patient map of systemic lupus erythematosus reveals disease-related multicellular immune programs conserved between blood and kidney

Systemic lupus erythematosus (SLE) shows marked clinical and molecular heterogeneity, yet patient stratification often relies on gene expression signatures lacking multicellular context. Here we construct a transcriptional patient map of SLE by analyzing 1,167 total samples (783 SLE, 384 healthy controls) across different resolutions, including single-cell and bulk blood as well as spatially resolved kidney tissue transcriptomes. Using an unsupervised approach we inferred patient-level transcriptomic immune programs from two independent single-cell RNA sequencing cohorts of peripheral blood mononuclear cells (PBMCs), capturing both differences between SLE and health as well as within-SLE heterogeneity. Specifically, we identified four conserved programs comprising two multicellular inflammatory programs driven by interferon and TNF/NFkB activity across immune cells, and two cell type-specific programs reflecting CD8 T cell cytotoxicity and a CD4 T cell naive-to-effector state. Functional analysis of these programs revealed a rewiring of both cell-to-cell interactions and task allocation across cell types during disease activation. In addition, mapping these programs onto an external longitudinal blood transcriptomic cohort predicted flare risk and identified candidate blood protein biomarkers detectable by proteomics. Finally, we showed that these blood programs were enriched in immune-infiltrated glomerular regions from kidney biopsies of individuals with lupus nephritis using spatially resolved transcriptomic data, thereby linking systemic immune programs to local tissue pathology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/721379v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e75f00org.highwire.dtl.DTLVardef@10e0a63org.highwire.dtl.DTLVardef@cc194forg.highwire.dtl.DTLVardef@191b4d2_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Synergistic effects of deleting the tyrosine phosphatases Shp1 and Shp2 on megakaryopoiesis and thrombopoiesis in mice

The Src homology 2 (SH2) domain-containing non-transmembrane protein-tyrosine phosphatases 1 and 2 (Shp1 and Shp2) have been implicated in regulating signaling from a variety of receptors and cell types, including the thrombopoietin (Tpo) receptor Mpl in megakaryocytes (MKs) and platelets. We previously showed that deletion of Shp1 and Shp2 in the MK/platelet lineage in mice using the Pf4-Cre transgene/loxP system impairs megakaryopoiesis and thrombopoiesis. However, we also observed unexpected phenotypes including a motheaten-like phenotype in Shp1-deficient mice and severe myelofibrosis in mice lacking both phosphatases. To determine whether these were lineage-specific effects, we utilized the Gp1ba-Cre transgenic mouse to delete loxP-flanked Shp1 and Shp2 in mice. Bone marrow-derived MKs from these mice expressed approximately 20-25% of Shp1 and Shp2, whereas platelets contain 5-10% of each phosphatase compared with controls. Minor MK/platelet defects were observed in mice lacking either Shp1 or Shp2 alone, however mice lacking both Shp1 and Shp2 exhibited macrothrombocytopenia, mild bleeding following tail injury, and impaired GPVI-mediated platelet aggregation and Syk phosphorylation, associated with reduction GPVI and integrin 2 subunit expression. Reduced Shp1 and Shp2 expression resulting in a significant reduction in ploidy, a block in MK maturation and proplatelet-producing MKs. Tpo-mediated Ras/MAPK signaling was reduced in Shp1/2-deficient MKs. Treatment of MKs with structurally distinct Shp2 allosteric inhibitors recapitulated key aspects of the Shp2-deficient phenotype, including aberrant megakaryopoiesis and reduced Mpl signaling. Our study highlights the synergistic functions of Shp1 and Shp2 in the MK/platelet lineage, and identifies Shp2 as a potential therapeutic target in myeloproliferative neoplasms. Key PointsO_LIDeletion of Shp1 and Shp2 in the MK/platelet lineage in mice results in macrothrombocytopenia and minor effects on platelet function. C_LIO_LIDefects can be partially explained by reduced Mpl signaling and aberrant megakaryopoiesis in the absence of Shp2 activity. C_LI

cell biology↗

bioRxiv2025

ParTIpy: A Scalable Framework for Archetypal Analysis and Pareto Task Inference

MotivationTrade-offs between different functions or tasks are pervasive across scales in biological systems. For example, individual cells cannot perform all possible functions simultaneously; instead they allocate limited resources to specialize in subsets of tasks by activating specific gene expression programs. Pareto Task Inference (ParTI) is a framework for analyzing biological trade-offs grounded in the theory of multi-objective optimality. However, existing software implementations of ParTI lack scalability to large datasets and do not integrate well with standard biological data analysis workflows, especially in the context of single-cell transcriptomics, limiting broader adoption. ResultsWe have developed ParTIpy (Pareto Task Inference in Python), an open-source Python package that combines advances in optimization and coreset methods to scale archetypal analysis, the primary algorithm underlying ParTI, to large-scale datasets. By providing additional tools to characterize archetypes, comprehensive documentation, and adopting standard scverse data structures, ParTIpy facilitates seamless integration into existing analysis workflows and broadens accessibility, particularly within the single-cell community. We demonstrate how ParTIpy can be used to study intra-cell-type gene expression variability through the lens of task allocation, offering a principled alternative to methods that impose discrete cell state classifications on inherently continuous variation. Availability and implementationParTIpys open-source code is available on GitHub (https://github.com/saezlab/ParTIpy) and pypi (https://pypi.org/project/partipy). Documentation is available at https://partipy.readthedocs.io. The code to reproduce the results of this paper is on GitHub (https://github.com/saezlab/ParTIpy_paper)

bioinformatics↗

bioRxiv2025

Environmental cues shape extracellular vesicles biogenesis and function in Streptococcus pneumoniae

The Gram-positive human pathogen Streptococcus pneumoniae adapts its metabolism to the environment during colonization and host invasion. Extracellular vesicles (EVs) are produced by S. pneumoniae in the process of infection but the exact interplay between metabolic adaptation and vesicle formation remains elusive. Here, we demonstrate that exposure to normal human serum induced rearrangement of the pneumococcal cell wall and significantly increased Sp-EVs production. Temperature and pH were critical factors for Sp-EVs formation: 37{degrees}C supported optimal EV production, while bacterial exposure to either basic or acidic environments slowed down pneumococcal EV biogenesis and led to a heterogeneous subpopulation profile. Proteomic analysis revealed that Sp-EVs are enriched in carbon metabolism-related proteins, specially those associated with glycolysis (e.g. eno, gapA, gapN, gpmA, pfkA, pykF, and tpi). Low glucose availability enhanced Sp-EVs production and intracellular ATP level, underlying a relation between metabolic status and EV biogenesis. Functionally, Sp-EVs promoted biofilm formation in both S. pneumoniae and Streptococcus pyogenes. Sp-EVs isolated under glucose-rich conditions enhanced S. pneumoniae biofilms, whereas Sp-EVs from glucose-poor conditions strongly stimulated S. pyogenes biofilm formation. These findings underscore the role of host and environmental cues in shaping pneumococcal EV production, composition, and function, highlighting their potential involvement in metabolic adaptation and interspecies interactions. ImportanceStreptococcus pneumoniae remains a leading cause of morbidity and mortality worldwide, responsible for diseases ranging from community-acquired pneumonia to meningitis and sepsis. It is of great concern in children under the age of five and in low-income countries, despite the existence of vaccination. The success of this pathogen relies on its capacity to adapt to diverse host niches, including the blood, nasopharynx and the lungs. Bacterial extracellular vesicles (EVs) have emerged as mediators of virulence and communication, yet their regulation by environmental and metabolic factors remains poorly understood. By exploring how environmental conditions and nutrient availability shape pneumococcal EV production and how these vesicles contribute to biofilm formation and interspecies interactions, our study contributes to the understanding of how S. pneumoniae applies complex strategies to persist and spread, with potential future applications in infection control and therapeutic strategies.

microbiology↗

bioRxiv2025

K5 polysaccharides inhibit SARS-CoV-2 infection by preventing spike-proteolytic priming

SARS-CoV-2 spike glycoprotein is a promising drug target due to its crucial role in viral infection. Heparin, a long linear polysaccharide that inhibits SARS-CoV-2 infection by acting on spike, has limited antiviral applications due to its anticoagulant effect. E. coli K5 polysaccharides share the same structure as the heparin precursor and can be chemically modified to devoid anticoagulant activity. Here, biochemical assays and computer simulations reveal that K5 with a high degree of sulfation at O-(K5OSH) or N- and O-positions (K5NOSH) bind spike with higher affinity than heparin, preventing its binding to ACE2 and cleavage by furin. This mechanism is supported by a cell syncytia assay showing that K5OSH and K5NOSH inhibit viral infection by blocking membrane fusion. Infection assays for SARS-CoV-2 Wuhan-Hu-1 and Omicron BA.1 variants corroborate their antiviral activity. These results support the therapeutic potential of K5OSH and K5NOSH against SARS-CoV-2, with K5OSH displaying the more promising activity profile.

biochemistry↗

bioRxiv2025

CellFlow enables generative single-cell phenotype modeling with flow matching

High-content phenotypic screens provide a powerful strategy for studying biological systems, but the scale of possible perturbations and cell states makes exhaustive experiments unfeasible. Computational models that are trained on existing data and extrapolate to correctly predict outcomes in unseen contexts have the potential to accelerate biological discovery. Here, we present CellFlow, a flexible framework based on flow matching that can model single cell phenotypes induced by complex perturbations. We apply CellFlow to various phenotypic screens, accurately predicting expression responses to a wide range of perturbations, including cytokine stimulation, drug treatments and gene knockouts. CellFlow successfully modeled developmental perturbations at the whole-embryo scale and guided cell fate and organoid engineering by predicting heterogeneous cell populations arising from combinatorial morphogen treatments and by performing a virtual organoid protocol screen. Taken together, CellFlow has the potential to accelerate discovery from phenotypic screens by learning from existing data and generating phenotypes induced by unseen conditions.

bioinformatics↗

bioRxiv2023

An Environmental Restriction impairs HIV-1 virion fusion and triggers innate immune recognition

In vivo, HIV-1 replicates within tissue, but how three-dimensional (3D) tissue-like environments influence viral spread and pathogenesis remains largely unknown. We previously identified an Environmental Restriction to cell-free Virus Infectivity (ERVI), imposed by collagen-rich 3D extracellular matrix (ECM), which diminishes HIV-1 particle infectivity. Here we report that ERVI is broadly implemented by various adhesive ECM components assembled into tissue-like 3D scaffolds. This restriction rapidly reduces infectivity within minutes, is saturable, and affects diverse primary HIV-1 strains and virions with distinct viral glycoproteins by impairing their ability to fuse with target cells. Importantly, particles subjected to ERVI also trigger pronounced pro-inflammatory cytokine secretion by monocyte-derived macrophages. Mechanistic analyses reveal that transient contact with collagen fibers induces conformational changes in the viral envelope glycoprotein (Env) and enhance its recognition by toll-like receptor (TLR) 2. This recognition promotes routing of viral particles into TLR8-positive endosomes, amplifying innate immune sensing of viral RNA genomes. ERVI thus acts via a dual mechanism: directly limiting the fusogenicity of cell-free virions and sensitizing them for innate immune detection. These findings highlight the biophysical properties of the ECM as a previously unrecognized, tissue-intrinsic barrier that restricts HIV-1 spread and promotes local inflammation representing a novel, broadly acting arm of antiviral innate immunity.

immunology↗

bioRxiv2023

The role of pneumococcal extracellular vesicles on the pathophysiology of the kidney disease Hemolytic Uremic Syndrome

Streptococcus pneumoniae-induced hemolytic uremic syndrome (Sp-HUS) is a kidney disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. This disease is frequently underdiagnosed and its pathophysiology is poorly understood. In this work, we compared clinical strains, isolated from infant Sp-HUS patients, to a reference pathogenic strain D39, for host cytotoxicity and further explored the role of Sp-derived extracellular vesicles (EVs) in the pathogenesis of a HUS infection. In comparison with the WT strain, pneumococcal HUS strains caused significant lysis of human erythrocytes and increased the release of hydrogen peroxide. Isolated Sp-HUS EVs were characterized by performing dynamic light-scattering microscopy and proteomic analysis. Sp-HUS strain released EVs at a constant concentration during growth, yet the size of the EVs varied and several subpopulations emerged at later time points. The cargo of the Sp-HUS EVs included several virulence factors at high abundance, i.e., the ribosomal subunit assembly factor BipA, the Pneumococcal Surface Protein A (PspA), the lytic enzyme LytC, several sugar utilization and fatty acid synthesis proteins. Sp-HUS EVs strongly downregulated the expression of the endothelial surface marker PECAM-1 and were internalized by human endothelial cells. Sp-HUS EVs elicited the release of pro-inflammatory cytokines (IL-1{beta}, IL-6) and chemokines (CCL2, CCL3, CXCL1) by human monocytes. These findings shed new light on the overall function of Sp-EVs, in the scope of infection-mediated HUS, and suggest new avenues of research for exploring the usefulness of Sp-EVs as therapeutic and diagnostic targets. ImportanceStreptococcus pneumoniae is a life-threatening human pathogen associated with severe illnesses in the upper respiratory tract. Disseminated infections also occur, as the kidney disease hemolytic uremic syndrome. Even though vaccination is available, this pathogen is responsible for a worldwide high mortality rate, especially among children from least developed countries, where vaccination strategies are poor or inexistent. It is estimated that 30% of invasive pneumococcal diseases are caused by antibiotic resistant bacteria, leading to the classification of "serious threat" by the World Health Organization. In order to prevent cases of severe illness, investigation in the direction of new vaccine candidates is of upmost importance. Pneumococcal extracellular vesicles pose as ideal candidates for a serotype-independent vaccine formulation. To this purpose, the aspects of vesicle formation, cargo allocation and function need to be understood in detail. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/526387v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1f5faeborg.highwire.dtl.DTLVardef@2c6176org.highwire.dtl.DTLVardef@1b29245org.highwire.dtl.DTLVardef@a119ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

SARS-CoV-2 nsp3-4 suffice to form a pore shaping replication organelles

Coronavirus replication is associated with the remodeling of cellular membranes resulting in the formation of double-membrane vesicles (DMVs). Recently, a pore spanning DMV was identified as a putative portal for viral RNA transcription and replication products providing a novel target for antiviral intervention. However, the exact components and the structure of the SARS-CoV-2 pore remain to be determined. Here, we investigate the structure of DMV pores by in situ cryo-electron tomography combined with subtomogram averaging. We reveal non-structural proteins (nsp) 3 and 4 as minimal components forming a DMV spanning pore and show that nsp3 Ubl1-Ubl2 domains are critical for inducing membrane curvature and DMV formation. Altogether, SARS-CoV-2 nsp3-4 has a dual role by driving the biogenesis of replication organelles and forming DMV-spanning replicopores. One-Sentence SummaryBiogenesis of SARS-CoV-2 replication organelles is driven by nsp3-4 constituting the double-membrane vesicle spanning pore.

microbiology↗

bioRxiv2021

Adipogenic activity of chemicals used in plastic consumer products

Bisphenols and phthalates, chemicals frequently used in plastic products, promote obesity in cell and animal models. However, these well-known metabolism disrupting chemicals (MDCs) represent only a minute fraction of all compounds found in plastics. To gain a comprehensive understanding of plastics as a source of exposure to MDCs, we characterized all chemicals present in 34 everyday products using nontarget high-resolution mass spectrometry and analyzed their joint adipogenic activities by high-content imaging. We detected 55,300 chemical features and tentatively identified 629 unique compounds, including 11 known MDCs. Importantly, chemicals that induced proliferation, growth, and triglyceride accumulation in 3T3-L1 adipocytes were found in one third of the products. Since the majority did not target peroxisome proliferator-activated receptor {gamma}, the effects are likely to be caused by unknown MDCs. Our study demonstrates that daily-use plastics contain potent mixtures of MDCs and can, therefore, be a relevant yet underestimated environmental factor contributing to obesity. TeaserPlastics contain a potent mixture of chemicals promoting adipogenesis, a key process in developing obesity.

pharmacology and toxicology↗

bioRxiv2021

The FDA-approved drug cobicistat synergizes with remdesivir to inhibit SARS-CoV-2 replication

Combinations of direct-acting antivirals are needed to minimize drug-resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and testing of a number of drug regimens has led to conflicting results. Here we show that cobicistat, which is an-FDA approved drug-booster that blocks the activity of the drug metabolizing proteins Cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Cell-to-cell membrane fusion assays indicated that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with the putative CYP3A target and nucleoside analog remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. The cobicistat/remdesivir combination was able to potently abate viral replication to levels comparable to mock-infected cells leading to an almost complete rescue of infected cell viability. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19.

microbiology↗

bioRxiv2021

Locally confined IFNγ production by CD4+ T cells provides niches for murine cytomegalovirus replication in the salivary gland

Cytomegalovirus (CMV) has evolved a unique virus-host relationship in the salivary glands (SGs) to sustain prolonged viral replication and hence chances for horizontal transmission. Previous reports have established a decisive role for IFN{gamma} producing CD4+ T cells to control murine CMV (MCMV) infection in the SGs; however, micro-anatomical information regarding their mode of action is largely missing. Here, we provide a spatiotemporal analysis of defined antiviral immune actions that eventually culminate in control of lytic MCMV replication in this preferred mucosal niche. CXCR3-mediated guidance of CD4+ T cells towards CXCL9 and CXCL10 expressing cells resulted in discrete clusters close to infection foci where they reported TCR engagement and produced IFN{gamma}. Of note, these clusters occasionally contained CD11c+ antigen-presenting cells with engulfed virus-associated remnants, most likely apoptotic bodies derived from previously infected cells, enabling antigen presentation to CD4+ T cells. The induced IFN{gamma} production within these CD4+ T cell accumulations triggered IFN{gamma}R signaling in a confined perimeter, thereby inducing local, but not organ-wide protection, and allowing MCMV replication to continue at not yet protected sites. Combining experimental data with a mathematical model of the spatiotemporal dynamics of infection and CD4+ T cell dynamics revealed a scenario, in which ultimate MCMV control is achieved through accumulating sites of regionally-confined tissue protection.

immunology↗