Biology subjects

Jantsch, J.

Publications and source records attributed to Jantsch, J..

6 recordsLinked to original sources

bioRxiv2026

Machine learning-guided discovery of a conserved plasmid proteomic signature enables MALDI-TOF MS detection of pOXA-48-carrying Enterobacterales

OXA-48 carbapenemases are among the most widespread and important resistance mechanisms in Enterobacterales. Yet detecting carbapenemases by conventional workflows necessitates additional testing, thus delaying optimization of therapy and implementation of infection control measures. Here, we present a machine learning approach that identifies the conserved pOXA-48 plasmid directly from routine MALDI-TOF spectra acquired for species identification. The model detects pOXA-48 carriers with an AUROC of 0.96-0.98 across two independent hospital cohorts and instrument platforms, indicating near-perfect discrimination. Using bottom-up proteomics, plasmid conjugation, and plasmid curing, we link the discriminative MALDI-TOF spectral features to proteins encoded on pOXA-48, with DUF1496 domain-containing protein producing the most discriminative spectral feature. Our approach reframes the resistance prediction task from inferring a resistance phenotype to detecting a conserved plasmid through its expressed proteomic signature and has the potential to enable rapid MALDI-TOF MS-based diagnostics for a wide range of plasmid-based resistance determinants.

microbiology↗

bioRxiv2026

DESI-MS-Based Analysis of Drug Distribution in Human Renal Cystic Tissue Using the Chorioallantoic Membrane (CAM) as a 3D In Vivo Model

The chorioallantoic membrane (CAM) model represents a promising three-dimensional in vivo platform for preclinical drug testing in human tissues. In this study, we investigated whether the tissue penetration and distribution of benzbromarone, a known inhibitor of the Ca2+ activated chloride channel TMEM16A and potential therapeutic agent for autosomal dominant polycystic kidney disease (ADPKD), can be successfully visualized in human renal cyst tissue cultured on the CAM. To this end, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) combined with an ultrahigh-resolution time-of-flight mass spectrometer was employed. We achieved spatially resolved molecular mapping of endogenous metabolites and lipids as well as the applied compound. MSI enabled clear differentiation between CAM and cystic tissue based on their distinct lipid profiles. Benzbromarone was reproducibly detected in the cyst specimens and exhibited selective accumulation along the cyst epithelium, which is considered the principal site of action. These observations were complemented by multivariate analyses including Uniform Manifold Approximation and Projection (UMAP), and sparse multinomial logistic zero-sum classification. The data-driven approach confirmed molecular differences between tissue types and allowed accurate classification of drug-treated and untreated regions. This study demonstrates that topically applied benzbromarone penetrates human renal cyst tissue in the CAM model and localizes to pharmacologically relevant tissue regions, notably the location of the Ca2+ activated chloride channel TMEM16A in the epithelial lining. The integration of high-resolution DESI-MSI with advanced statistical analysis provides a robust and label-free method to study drug distribution in human tissue grafts. Our findings contribute to the advancement of translational research in analytical chemistry and pharmacology.

biochemistry↗

bioRxiv2026

NLRP3 activators disrupt the endocytic AP2 complex and plasma membrane signaling

Organellar perturbations are linked to NLRP3 inflammasome activation, however, it remains unclear whether unrelated agonists converge on a common upstream pathway. Here, we traced intracellular organelle and protein movements by differential ultracentrifugation combined with mass spectrometry-based proteomics. We show that NLRP3 activators uniformly disrupt the endocytic Adaptor Protein 2 (AP2) complex, whereas other subcellular rearrangements are stimulus-specific. We discovered Dynasore as a K-efflux-independent NLRP3 activator that engages this signaling node irrespective of endocytosis inhibition. Pharmacological and genetic perturbation of AP2 renders cells unresponsive to extracellular cues, blunting GPCR signaling, cAMP production, and chemotaxis, thereby enforcing a frozen signaling state that propagates NLRP3 inflammasome activation. Collectively, our study reveals a common surveillance checkpoint linking impaired plasma membrane signaling to the execution of inflammation and cell death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707400v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@178eb1dorg.highwire.dtl.DTLVardef@193cb02org.highwire.dtl.DTLVardef@1f50080org.highwire.dtl.DTLVardef@1f3e3e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

The metabolic program of inflammatory eosinophils accounts for chronic parasite-induced skin-disease

Eosinophils exert antimicrobial, cytotoxic and immunoregulatory effects, but their function in cutaneous tissue still remains poorly understood. Here, we used a mouse model of chronic cutaneous leishmaniasis caused by the protozoan parasite Leishmania (L.) mexicana to investigate the function and transcriptomic signature of eosinophils in the skin. In C57BL/6 wild-type mice, L. mexicana infection induced local and systemic eosinophilia that was dependent on type 2 innate lymphoid cells and interleukin-5. Genetic and pharmacological depletion of eosinophils led to complete clinical resolution of disease, which was accompanied by a more pronounced Th1 and M1-like macrophage response. Bioinformatic analyses revealed a novel inflammatory and tissue-specific transcriptional trajectory in skin-infiltrating eosinophils. Skin-imprinted eosinophils strongly expressed the high-affinity glucose transporter 3 (Slc2a3), deprived the environment of glucose and directly impeded the function of Th1 cells. Together, our results demonstrate that disease progression and chronicity of L. mexicana infection is caused by inflammatory eosinophils and linked to their metabolic program. Short SummaryThe authors describe that depletion of eosinophils prevents chronic cutaneous disease caused by Leishmania mexicana. They identify a novel, tissue-specific transcriptomic profile of inflammatory skin eosinophils and demonstrate that skin-imprinted eosinophils show strong glucose uptake and directly repress Th1 responses. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/640104v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@3ecd3org.highwire.dtl.DTLVardef@1b1283forg.highwire.dtl.DTLVardef@1c941fdorg.highwire.dtl.DTLVardef@b7c39_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIEosinophil accumulation precedes the development of chronic cutaneous leishmaniasis C_LIO_LIEosinophil depletion or IL-5 neutralization lead to clinical cure of the disease C_LIO_LIL. mexicana infection elicits a unique transcriptomic signature of skin eosinophils C_LIO_LISkin eosinophils show a marked uptake of glucose and directly repress Th1 responses C_LI

immunology↗

bioRxiv2023

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (low serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that human hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis. SIGNIFICANCE STATEMENTFibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls phosphate and vitamin D metabolism. Excess FGF23 is postulated to cause left ventricular hypertrophy, while FGF23 deficiency reduces life span and mimics age-related diseases in mice. FGF23 is also a potential biomarker for chronic kidney disease and cardiovascular disorders, but its role in disease progression is unclear. Therefore, it is important to explore the regulation of FGF23 production, which is incompletely understood. Our paper identifies extracellular-sodium-NFAT5 signaling as a key regulator of FGF23 formation.

physiology↗

bioRxiv2022

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis- aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, significant weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/-mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

immunology↗