Biology subjects

Dietschmann, A.

Publications and source records attributed to Dietschmann, A..

2 recordsLinked to original sources

bioRxiv2026

Local albumin excess exacerbates Candida albicans-induced inflammasome activation underlying the immunopathology of vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC) is a mucosal yeast infection where symptoms are driven by inflammatory responses. The onset of VVC is instigated by the yeast Candida albicans, but the underlying causes of disease-driving hyperinflammation remains incompletely resolved. We found that vaginal albumin concentrations are higher in women with recurrent VVC and during VVC in mice. These albumin levels correlated with inflammatory cytokines in vaginal lavages. While the abundance of this serum protein in the vagina can represent a hallmark of inflammation-induced vascular permeability, we reveal molecular mechanisms by which albumin also drives inflammation. It increased NLRP3 inflammasome activation in human macrophages elicited by C. albicans. Albumin induced fungal adaptations that increased resistance to macrophage-mediated clearance. Further it increased the expression of fungal secreted aspartic protease 1, which we identified as the effector driving inflammasome activation. Moreover, neutrophils show impaired effectivity in clearing C. albicans in presence of albumin. Collectively, vaginal albumin may not only be a consequence of inflammation of the vaginal mucosa, but also can drive hyperinflammatory responses that underlie immunopathology in VVC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/700771v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@f13fd5org.highwire.dtl.DTLVardef@95e58aorg.highwire.dtl.DTLVardef@11104dforg.highwire.dtl.DTLVardef@56e9be_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

IRF4 is a master regulator of multinucleated giant cell formation

Multinucleated giant cells (MGCs) are a hallmark pathological feature of a wide range of diseases, yet the mechanisms underlying their formation and function remain poorly understood. Although it is recognized that MGCs arise from a heterogeneous pool of myeloid precursors, how a committed MGC fate develops therein remains unknown. Here, combining temporal in vitro and in vivo differentiation of bone marrow-derived myeloid precursors with single cell and bulk RNA sequencing as well as CRISPR/Cas9-mediated gene editing, we shed insight into how MGCs emerge. Our findings reveal that coordinated upregulation of cell fusion genes and cellular metabolism, particularly oxidative phosphorylation, regulate the transition from macrophage progenitors to fusion competent cells. In vivo fate-mapping unveils Ms4a3-, and Cd11c-but not Cx3cr1-traced cells as the predominant precursor populations for MGCs in a lung granuloma formation model. Notably, transcription factor profiling in the progression from early myeloid precursors to pre-MGCs identifies IRF4 as a key molecular switch driving MGC generation. IRF4+ MGCs are present in different pathologies, including Schistosoma mansoni egg induced granulomas, Aspergillus fumigatus conidia mediated allergic airway inflammation and human head and neck squamous cell carcinomas. Mechanistically, IRF4 controls critical fusion related genes such as Dcstamp and Ocstamp. Consequently, Irf4 deficient cells are unable to develop into MGCs. Collectively, our work delineates the trajectory of MGC differentiation, establishing IRF4 as a defining transcription factor required for the generation of fusion-competent progenitors that ultimately give rise to MGCs.

immunology↗