{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T02:32:44Z","timestamp":1794018764486,"version":"4.8.0"},"posted":{"date-parts":[[2026,2,14]]},"group-title":"Immunology","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  People with chronic hyperglycemia are more susceptible to fungal skin infections, but the mechanisms underlying their worse clinical outcomes remain unclear. Using both\n                  <jats:italic>in vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vitro<\/jats:italic>\n                  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\n                  <jats:italic>Candida albicans<\/jats:italic>\n                  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\n                  <jats:italic>C. albicans<\/jats:italic>\n                  -infected dermal macrophages cultured in high glucose showed enrichment of genes related to antimicrobial effectors and the C-type lectin receptor pathway, including\n                  <jats:italic>Clec7a<\/jats:italic>\n                  (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\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Mechanistically, Dectin-1 signaling in hyperglycemia promoted increased prostaglandin E\u2082 (PGE\u2082) production via induction of microsomal Prostaglandin E Synthase-1 (mPGES-1), and inhibition of PGE\u2082 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.\n                <\/jats:p>","DOI":"10.64898\/2026.02.11.705431","type":"posted-content","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:50:21Z","timestamp":1771069821000},"source":"Crossref","is-referenced-by-count":2,"title":["Hyperglycemia promotes maladaptive Dectin-1 signaling and impairs skin antifungal host defense"],"prefix":"10.64898","author":[{"given":"Dante E.","family":"Reyna","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C. G.","family":"Salina","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amondrea","family":"Blackman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7925-449X","authenticated-orcid":false,"given":"Ruben","family":"Martinez-Barricarte","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Doran","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5363-415X","authenticated-orcid":false,"given":"C. Henrique","family":"Serezani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"},{"name":"Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021623150939000_2026.02.11.705431v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119"},{"key":"2026021623150939000_2026.02.11.705431v1.2","unstructured":"IDF Diabetes Atlas 2025 [Internet]. Diabetes Atlas. [cited 2025 Sep 15]. 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