Antimicrobial resistance has made infections a growing global health threat. Among these, fungal pathogens—especially the WHO ‘Critical Priority’ pathogen Candida albicans—cause more annual deaths than influenza or malaria yet remain understudied. Concurrently, metabolic diseases affect an ever-growing number of people worldwide, causing significant morbidity and mortality. People living with diabetes, a condition characterised by elevated blood glucose, face an increased risk of life-threatening bloodstream infections with Candida. However, the mechanisms underlying increased susceptibility to these and other deadly infections in diabetes remain unresolved.
We used a genetic mouse model of type 2 diabetes to study which factors of the metabolic disease drive worse outcomes of invasive fungal infection. We infected diabetic and control mice with Candida via tail vein injections and assessed disease severity, host immune response, and pathogen load and phenotype, as well as glucose levels in the blood and kidneys, the main site of infection. Diabetic animals displayed more severe disease, including ~7-fold higher fungal burden and worse survival compared to healthy controls, despite evidence of mounting an immune response. Levels of glucose, a preferred carbon source for Candida, were elevated in diabetic kidneys at baseline and dropped to control levels with infection. Fungi present within diabetic kidneys had higher expression of glycolysis genes than those from controls. Differences in susceptibility between diabetic and control mice diminished when infected animals were infected with the Candida tye7Δ/Δgal4Δ/Δ mutant, which is less able to upregulate glucose utilisation.
Our data suggest that high glucose levels in diabetic animals allow Candida to rapidly outgrow host immune responses and cause exacerbated disease. Our findings hold relevance for other infections with glucose-utilising pathogens and highlight the importance of adequate glycaemic control in individuals living with diabetes.