Immunometabolic and epigenetic dysregulation of oral mucosal immunity in diabetes-associated candidiasis

The National Institute of Dental and Craniofacial Research awarded the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center $474,557 on August 1, 2026, under the Oral Diseases and Disorders Research program (CFDA 93.121) to investigate immunometabolic and epigenetic dysregulation of oral mucosal immunity in diabetes-associated candidiasis.

The research addresses mechanisms by which hyperglycemia increases susceptibility to oropharyngeal candidiasis (oral thrush), an opportunistic infection caused by Candida albicans that occurs at substantially higher incidence and severity in individuals with poorly controlled diabetes. Current knowledge gaps limit understanding of how chronic metabolic disease alters oral mucosal immunity and hinder development of targeted therapies. The investigator's central hypothesis, supported by preliminary data, is that hyperglycemia enhances susceptibility by suppressing hypoxia-inducible factor 1-alpha (HIF-1a) signaling and impairing proline catabolism, leading to epithelial barrier dysfunction, altered mucosal immunity, and increased pyroptosis during C. albicans infection. The research will delineate mechanisms by which hyperglycemia-induced suppression of HIF-1a drives epithelial barrier dysfunction and pyroptosis, with the long-term goal of identifying therapeutic targets that restore mucosal immunity and mitigate infection risk.

The award funds research performed in Torrance, California, with a performance period of August 1, 2026, through July 31, 2028.

Abstract

Diabetes increases susceptibility to infectious diseases, including oropharyngeal candidiasis (OPC, or thrush), an opportunistic infection caused by the commensal fungus candida albicans. Both the incidence and severity of OPC are substantially higher in individuals with poorly controlled diabetes. Despite its clinical significance, there are no targeted therapies for diabetic OPC, largely because the mechanisms by which hyperglycemia increase susceptibility to OPC remain unknown. The oral mucosal tissue acts as both a physical barrier and an active immune sentinel against C. Albicans. However, how chronic metabolic disease, especially diabetes, alters oral mucosal immunity remains incompletely understood. This critical knowledge GAP limits our understanding of host-fungal interactions in the oral mucosa and hinders the development of effective therapeutic interventions. Our long-term goal is to define the molecular mechanisms underlying OPC susceptibility in diabetes and to identify therapeutic targets that restore mucosal immunity and mitigate infection risk. The objective of this research is to determine how hyperglycemia alters epithelial immunometabolism and epigenetic regulation to drive barrier dysfunction and susceptibility to oral C. Albicans infection. Our central hypothesis, supported by strong preliminary data, is that hyperglycemia enhances OPC vulnerability by suppressing hypoxia-inducible factor 1-alpha (HIF-1Α) signaling and impairing proline catabolism, leading to epithelial barrier dysfunction, altered mucosal immunity, and increased pyroptosis during C. Albicans infection (aim 1 and 2). In aim 1, we will delineate the mechanisms by which hyperglycemia- induced suppression of HIF-1Α drives epithelial barrier dysfunction and pyroptosis. Our working hypothesis is that hyperglycemia-induced accumulation of TCA cycle intermediates, particularly Α-ketoglutarate, suppresses HIF-1Α signaling, resulting in barrier disruption and activation of pyroptosis during C. Albicans infection. In aim 2, we will determine how hyperglycemia dysregulates proline metabolism and impairs epithelial memory, a novel non-hematopoietic mechanism of trained immunity, during mucosal candidiasis. Our working hypothesis is that hyperglycemia impairs proline catabolism and epithelial memory, as evidenced by elevated intracellular proline levels and reduced prodh expression during infection. The proposed research is significant because IT will reveal how hyperglycemia increases OPC susceptibility and identify therapeutic targets to restore oral mucosal immunity. These findings will fill a critical knowledge GAP in our understanding of host-fungal interactions within the oral mucosa in diabetic patients and provide a foundation for developing targeted interventions to prevent opportunistic infections in the growing diabetic population.