Hyperglycemia-induced HIF-1α dysregulation drives epithelial barrier dysfunction and increases susceptibility to oral candidiasis

Introduction/Rationale: Diabetes increases susceptibility to infectious diseases, including oropharyngeal candidiasis (OPC, or thrush), an opportunistic infection caused by the commensal fungus Candida albicans. Individuals with poorly controlled diabetes exhibit a higher incidence and severity of OPC. Despite its clinical relevance, there are currently no targeted therapies for diabetic OPC, largely because the mechanisms by which hyperglycemia increase OPC susceptibility and alter oral mucosal immunity remain unknown.

Methods: Studies were conducted using hyperglycemic human oral epithelial cells, and physiological relevance was confirmed using streptozotocin-induced diabetic mouse models. Readouts including fungal burden, immune responses, and metabolite profiling were analyzed following C. albicans infection

Results: We identified that hyperglycemia enhances susceptibility to OPC by impairing hypoxia-inducible factor 1-alpha mediated epithelial barrier function and mucosal immunity during C. albicans infection. Mechanistically, hyperglycemia or HIF-1α knockdown suppressed claudin-1 expression, a tight junction protein regulated by HIF-1α, leading to epithelial barrier dysfunction. Additionally, hyperglycemia promoted epithelial pyroptosis, an inflammatory form of cell death, through HIF-1α-dependent activation of cleaved gasdermin D during infection. Furthermore, hyperglycemia induced dysregulated proline metabolism, characterized by elevated proline levels and reduced expression of proline dehydrogenase, which contributed to aberrant inflammation and impaired epithelial immunity during infection.

Conclusion: Our findings highlight the critical role of HIF-1α in regulating epithelial barrier integrity and pyroptosis, suggesting it as a potential therapeutic target for mucosal fungal infections in patients with diabetes. This work provides novel insights into host-pathogen interactions under hyperglycemic conditions and identifies potential targets for the management of diabetes-associated mucosal infections.