Biology subjects

Schleicher, U.

Publications and source records attributed to Schleicher, U..

4 recordsLinked to original sources

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↗

bioRxiv2025

Quantitative proteomics of infected macrophages reveals novel Leishmania virulence factors

Leishmaniasis is a major public health problem, causing diseases ranging from self-healing skin lesions to life-threatening chronic infections. Understanding how Leishmania parasites evade the host defense system is crucial for understanding the different manifestations of the disease and for improving diagnostic tools and drug development. We performed high-resolution proteome profiling of Leishmania spp. across three species during macrophage infection and identified distinct temporal expression patterns. Clustering analysis revealed unique protein expression profiles for each Leishmania species, whereas pairwise enrichment analysis revealed specific up- and downregulation patterns at different infection stages. Our results confirmed known virulence factors and highlighted new ones, demonstrating the utility of our dataset. We validated the dataset by showing that deletion of putative L. mexicana virulence factors resulted in reduced stage differentiation capacity and infectivity. This novel Leishmania infectome database (LInfDB) is available online for further exploration (https://butterlab.imb-mainz.de/LInfDB), providing a valuable resource for future research.

microbiology↗

bioRxiv2024

The histone methyltransferase DOT1B is dispensable for stage differentiation and macrophage infection in Leishmania mexicana

Conserved histone methyltransferases of the DOT1 family are involved in replication regulation, cell cycle progression, stage differentiation and gene regulation in trypanosomatids. However, the specific functions of these enzymes depend on the host evasion strategies of the parasites. In his study, we investigated the role of DOT1B in Leishmania mexicana, focusing on life cycle progression and infectivity. In contrast to Trypanosoma brucei, in which DOT1B is essential for the differentiation of mammal-infective bloodstream forms to insect procyclic forms, L. mexicana DOT1B (LmxDOT1B) is not critical for the differentiation of promastigotes to amastigotes in vitro. Additionally, there are no significant differences in the ability to infect or differentiate in macrophages or sand fly vectors between the LmxDOT1B-depleted and control strains. These findings highlight the divergency of the function of DOT1B in these related parasites, suggesting genus-specific adaptations in the use of histone modifications for life cycle progression and host adaptation processes.

microbiology↗

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↗