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Diabetes and Immunosuppression Drive Distinct Patterns of Candidozyma auris Skin Colonization and Dissemination in
Kaustav Das Gupta1, Derek Quintanilla1, Eman G Youssef1
1Division of Infectious Diseases, The Lundquist Institute at Harbor- University of California at Los Angeles Medical Center, Torrance, California, USA.
Abstract:
Candidozyma auris is an emerging, multidrug-resistant (MDR) fungal pathogen that persistently colonizes human skin and disproportionately causes invasive infections in patients with metabolic or immune dysfunction. Despite strong epidemiological links to diabetes and immunosuppression, how these host conditions shape skin colonization, immune defense, and dissemination remain poorly defined. Here, we establish complementary murine model of C. auris skin colonization under immunocompetent, immunosuppressed, and diabetic ketoacidosis (DKA) conditions. DKA mice exhibited significantly increased skin fungal burden, impaired clearance, and frequent systemic dissemination. Notably, DKA permitted dissemination despite preserved granulocyte and neutrophil recruitment to the skin, indicating a functional rather than quantitative defect in innate immunity. Consistent with this, phagocytes from DKA mice displayed impaired antifungal activity characterized by reduced phagocytosis and killing despite elevated reactive oxygen species production. Hyperglycemic and ketone-rich conditions (BHB) remodel the C. auris cell wall, reducing mannan, increasing chitin, and upregulating adhesins, thereby enhancing adhesion and inflammatory activation while impairing neutrophil killing. Together, these findings reveal host metabolic dysfunction as a primary driver of persistent C. auris skin colonization and dissemination, identify qualitative defects in innate antifungal immunity as a key determinant of invasive risk and highlight metabolic condition as a critical target for infection prevention strategies.
Insights
Diabetic ketoacidosis (DKA) significantly increases Candida auris skin colonization and systemic spread by impairing innate immune cell function. This highlights metabolic dysfunction as a key factor in invasive fungal infections.
Area of Science:
- Mycology
- Immunology
- Infectious Diseases
Background:
- Candida auris is a multidrug-resistant fungus causing invasive infections, particularly in immunocompromised or metabolically compromised individuals.
- The precise mechanisms by which host metabolic conditions like diabetes influence C. auris skin colonization and dissemination are not well understood.
Purpose of the Study:
- To investigate the impact of diabetic ketoacidosis (DKA) and immunosuppression on Candida auris skin colonization and dissemination in a murine model.
- To elucidate the underlying defects in innate immunity contributing to increased fungal burden and systemic spread.
Main Methods:
- Development of a murine model simulating C. auris skin colonization under immunocompetent, immunosuppressed, and DKA conditions.
- Assessment of fungal burden, clearance, and systemic dissemination in each model.
- Evaluation of phagocyte function, including phagocytosis, killing activity, and reactive oxygen species production.
- Analysis of C. auris cell wall composition and adhesion properties under hyperglycemic and ketone-rich conditions.
Main Results:
- DKA mice showed significantly higher fungal burden, impaired clearance, and frequent dissemination compared to controls.
- Dissemination in DKA mice occurred despite normal neutrophil recruitment, indicating a functional defect in innate immunity.
- Phagocytes from DKA mice exhibited reduced phagocytosis and killing of C. auris, despite increased ROS production.
- Hyperglycemic and ketone-rich conditions altered the C. auris cell wall, enhancing adhesion and reducing susceptibility to neutrophil killing.
Conclusions:
- Host metabolic dysfunction, specifically DKA, is a major driver of persistent C. auris skin colonization and dissemination.
- Qualitative defects in innate antifungal immunity are critical determinants of invasive fungal infection risk.
- Metabolic status represents a crucial target for developing strategies to prevent C. auris infections.
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