Biology subjects

Lion, T.

Publications and source records attributed to Lion, T..

3 recordsLinked to original sources

bioRxiv2023

Proline catabolism is key to facilitating Candida albicans pathogenicity

Candida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and for growth. We report that put1-/- and put2-/- strains, carrying defective Proline UTilization genes, display remarkable proline sensitivity with put2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate P5C, which inhibits mitochondrial respiration. The put1-/- and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells colonizing a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not of put2-/- cells. Multiple members of the Candida species complex, including C. auris, are capable of using proline as a sole energy source. Our results indicate that a tailored proline metabolic network tuned to the mammalian host environment is a key feature of opportunistic fungal pathogens.

microbiology↗

bioRxiv2022

Cross-species analysis identifies conserved transcriptional mechanisms of neutrophil maturation

Neutrophils are evolutionarily conserved innate defense cells implicated in diverse pathological processes. Zebrafish models have contributed substantially to our understanding of neutrophil functions, but similarities to human neutrophil maturation have not been characterized limiting applicability to study human disease. We generated transgenic zebrafish strains to distinguish neutrophil maturation grades in vivo and established a high-resolution transcriptional profile of neutrophil maturation. We linked gene expression at each stage to characteristic transcription factors, including C/ebp{beta}, important for late neutrophil maturation. Cross-species comparison of zebrafish, mouse, and human confirmed high molecular similarity in immature stages and discriminated zebrafish-specific from pan-species gene signatures. Applying pan-species neutrophil maturation signatures in RNA-seq data from neuroblastoma patients revealed an association of metastatic tumor cell infiltration in the bone marrow with an increase in mature neutrophils. Our detailed neutrophil maturation atlas provides a valuable resource for studying neutrophil function at different stages across species in health and disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/518146v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@d46deaorg.highwire.dtl.DTLVardef@7c2647org.highwire.dtl.DTLVardef@b535eeorg.highwire.dtl.DTLVardef@e7dc38_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Nanopanel2 calls phased low-frequency variants in Nanopore panel sequencing data

Clinical decision making is increasingly guided by accurate and recurrent determination of presence and frequency of (somatic) variants and their haplotype through panel sequencing of disease-relevant genomic regions. Haplotype calling (phasing), however, is difficult and error prone unless variants are located on the same read which limits the ability of short-read sequencing to detect, e.g., co-occurrence of drug-resistance variants. Long-read panel sequencing enables direct phasing of amplicon variants besides having multiple other benefits, however, high error rates of current technologies prevented their applicability in the past. We have developed nanopanel2 (np2), a variant caller for Nanopore panel sequencing data. Np2 works directly on base-called FAST5 files and uses allele probability distributions and several other filters to robustly separate true from false positive calls. It effectively calls SNVs and INDELs with variant allele frequencies (VAF) as low as 1% and 5% respectively and produces only few low-frequency false-positive calls. Haplotype compositions are then determined by direct phasing. Np2 is the first somatic variant caller for Nanopore data, enabling accurate, fast (turnaround <48h) and cheap (sequencing costs ~10$/sample) diagnostic workflows.

bioinformatics↗