Doran, A. | Search bioRxiv

bioRxiv2026

Hyperglycemia promotes maladaptive Dectin-1 signaling and impairs skin antifungal host defense.

People with chronic hyperglycemia are more susceptible to fungal skin infections, but the mechanisms underlying their worse clinical outcomes remain unclear. Using both in vivo and in vitro models, we explored how hyperglycemia influences skin antifungal defenses and how GLP1 agonists might restore host defense in diabetic conditions. Hyperglycemic mice showed increased susceptibility to Candida albicans skin infections, with larger lesions and higher fungal loads at all time points tested. Histology revealed larger abscesses, more extensive myeloid cell infiltration, and poorer control of fungal invasion, associated with increased chemoattractant production on day 1 post-infection. Despite heightened inflammatory responses, macrophages and keratinocytes exposed to high glucose exhibit markedly impaired fungal ingestion. RNAseq analysis of C. albicans-infected dermal macrophages cultured in high glucose showed enrichment of genes related to antimicrobial effectors and the C-type lectin receptor pathway, including Clec7a (Dectin-1), while suppressing downstream signaling pathways required for effective phagocytosis. Pharmacologic blockade or genetic deletion of Dectin-1 restored fungal uptake under high-glucose conditions and improved host defense in vivo. Mechanistically, Dectin-1 signaling in hyperglycemia promoted increased prostaglandin E2 (PGE2) production via induction of microsomal Prostaglandin E Synthase-1 (mPGES-1), and inhibition of PGE2 synthesis rescued deficient phagocytic function. Finally, treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide reduced lesion size, fungal burden, inflammation, and tissue damage in diabetic mice, linking metabolic control to restoration of innate immune function. These findings identify maladaptive innate immune sensing as a key mechanism underlying susceptibility to fungal infection in diabetes and reveal how metabolic stress converts antifungal recognition pathways into drivers of inflammatory dysfunction.

immunology↗

bioRxiv2017

Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes

Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, we identified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 to 6 MYA, but that are absent in the Hominidae. In fact, Hominidae show between four-and seven-fold lower rates of nucleotide change and feature turnover in both neutral and functional sequences suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. For example, recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli. This process resulted in thousands of novel, species-specific CTCF binding sites. Our results demonstrate that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology.

genomics↗