LIN, J. | Search bioRxiv

bioRxiv2025

The acute sleep-inducing effects of light require histamine neurotransmission in mice

Sleep regulation depends on the complex interplay between homeostatic and circadian processes synchronized by the light/dark cycle. Sleep is also directly regulated by light via the retinal inputs to the preoptic area (POA). Although the light-responsive POA neurons project to several wake-promoting structures, including histaminergic neurons in the tuberomammillary nucleus (TMn), there is no functional evidence for their involvement in light-induced sleep. To bridge this gap, we used histidine decarboxylase (HDC, the histamine-synthetizing enzyme) knockout mice (HDC-/-, n=7) and hM4Di-HDC-cre mice (HDC+/+, n=8) subjected to an ultradian light/dark protocol (LD 1h:1h over 24h), and another group of hM4Di-HDC-cre mice (n=8) exposed to a 1-h light pulse. We found that light pulses during the biological night enhanced slow wave sleep and increased cortical EEG power in the delta range (0.5-3Hz), and that these effects were significantly attenuated both in HDC-/- (83 vs 23 min/6h, p=0.005) under LD 1h:1h condition and in hM4Di-HDC-cre mice after acute chemogenetic silencing of histamine neurons by the DREADD ligand deschloroclozapine (15 vs 6 min/h, p=0.0016) under a 1-h light pulse. In addition, the sleep-inducing effect of light was circadian dependent, with the strongest effect at the beginning and end of the night but no effect at all during the biological day in HDC+/+mice. Our study provides functional evidence that the acute sleep-inducing effects of light on sleep require histamine neurotransmission in mice.

neuroscience↗

bioRxiv2024

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage by Candida albicans

Candidalysin is a cytolytic peptide produced by the opportunistic fungal pathogen Candida albicans. This peptide is a key virulence factor in mouse models of mucosal and hematogenously disseminated candidiasis. Despite intense interest in the role of candidalysin in C. albicans pathogenicity, its host cell targets have remained elusive. To fill this knowledge gap, we performed a genome-wide loss-of-function CRISPR screen in a human oral epithelial cell line to identify specific host factors required for susceptibility to candidalysin-induced cellular damage. Among the top hits were XYLT2, B3GALT6 and B3GAT3, genes that function in glycosaminoglycan (GAG) biosynthesis. Deletion of these genes led to the absence of GAGs such as heparan sulfate on the epithelial cell surface and increased resistance to damage induced by both candidalysin and live C. albicans. Biophysical analyses including surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin physically binds to sulfated GAGs, facilitating its oligomerization or enrichment on the host cell surface. The addition of exogenous sulfated GAGs or the GAG analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate, but not non-sulfated dextran, also inhibited epithelial cell endocytosis of C. albicans and fungal-induced epithelial cell cytokine and chemokine production. In a murine model of vulvovaginal candidiasis, topical dextran sulfate administration reduced host tissue damage and decreased intravaginal IL-1{beta} and neutrophil levels. Collectively, these data indicate that GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

microbiology↗