Biology subjects

Jarosch, S.

Publications and source records attributed to Jarosch, S..

3 recordsLinked to original sources

bioRxiv2023

Spatial Transcriptomic Characterization of Novel Pathologic Niches in IPF

An unmet medical need persists in Idiopathic Pulmonary fibrosis (IPF), for which treatments additional to anti-fibrotic therapy are needed. Single cell RNA sequencing (scRNA-seq) has advanced our understanding of IPF with cell type-specific insights but lacks cellular tissue context. Spatial transcriptomics addresses this by providing spatially resolved gene expression, enabling gene and cell type localization within the tissue environment. We profiled IPF and control patient lung tissue sections using spatial transcriptomics and combined the data with an atlas of integrated IPF scRNA-seq datasets. Through computational analysis, we identified three disease-associated pathologic niches with unique cellular composition / localization and analyzed their cell-cell communication. We identified the Fibrotic niche, comprising Myofibroblasts and Aberrant Basaloid cells, preferentially located around airways and close to the Airway Macrophage niche in the lumen, containing SPP1+ Macrophages. We also identified the Immune niche, distinct foci of lymphoid cells in fibrotic tissue, surrounded by remodeled endothelial vessels. TEASERSpatial transcriptomics localizes genes and cell types in the tissue and identifies pathological cellular niches in IPF and control lungs.

systems biology↗

bioRxiv2023

Mitochondrial perturbation of the epithelium causes microbial dysbiosis and unresolved tissue injury in intestinal inflammation

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60{Delta}/{Delta}IEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60{Delta}/{Delta}IEC;AhR-/-) or IL-10 (Hsp60{Delta}/{Delta}IEC;Il10-/-) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60{Delta}/{Delta}IEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60{Delta}/{Delta}IEC mice with the synthetic community OMM12 confirms consistent expansion of metabolically-flexible Bacteroides spp. across all models and mono-colonization with B. caecimuris recapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, including Ido1, Nos2, and Duox2, distinguishing active from inactive tissue inflammation in 343 resected samples from Crohns disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/549844v6_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@240c5forg.highwire.dtl.DTLVardef@a84382org.highwire.dtl.DTLVardef@e829e3org.highwire.dtl.DTLVardef@163625_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Control of metabolic injury by microbial signals. C_FIG O_LIMitochondrial perturbation of the intestinal epithelium induces tissue injury C_LIO_LILoss of IL-10 and AhR-related host mechanisms accelerate injury and inflammation C_LIO_LIMitochondrial dysfunction induces dysbiosis and expansion of Bacteroides spp. C_LIO_LIMetabolic injury gene signature discriminates inflamed vs. non-inflamed IBD samples C_LI

microbiology↗

bioRxiv2022

High-resolution profiling of neoantigen-specific T cell receptor activation signatures links moderate stimulation patterns to resilience and sustained tumor control

Neoantigen-specific T cell receptors (neoTCRs) promise a safe, highly personalized therapeutic approach in anti-tumor immunotherapy. Substantial progress has been made regarding their identification whereas detailed functional assessment of single TCR characteristics impacting therapeutic efficacy is lacking. We previously identified and functionally characterized neoTCRs specific for neoepitopes derived from KIF2C and SYTL4 demonstrating differences in functional avidity in a patient with metastatic melanoma. In this work, we now combined single-cell TCR- and RNA-sequencing using stimulated peripheral blood derived CD8+ T cells of this patient and thereby identified two new neoTCRs recognizing the previously identified mutated epitope KIF2CP13L. Analyzing patient-derived neoTCR expressing T cells, we detected distinct activation patterns as a measure for substantial heterogeneity within oligoclonal T cell responses towards neoantigens upon specific ex vivo-restimulation. Moreover, neoTCR-transgenic T cells from healthy donors were employed for detailed in vitro and in vivo fine-characterization focusing on TCR-intrinsic functional patterns. Most importantly, in a xenogeneic mouse model experimentally simulating rechallenge of tumor infiltrating lymphocytes (TILs) after adoptive T cell transfer, we found that T cells expressing neoTCRs with a moderate activation profile provide a stable and more sustained anti-tumor response upon repeated in vivo tumor challenge as compared to neoTCRs with a stronger, burst-like reactivity. These insights have significant implications for engineering TCR-transgenic T cells for therapeutic purposes. One Sentence SummaryCombining TCR specificity linked single-cell transcriptomics with in vitro and in vivo characterization of transgenic T cells helps to decipher functional potential and persistence of neoantigen-specific T cell receptors (TCRs) for TCR-transgenic T cell-based adoptive cellular anti-tumor immunotherapy.

immunology↗